Toxic Nodular GoiterJohn H. Boey

ABSTRACTToxic nodular goiters comprise toxic multinodular goiter (TMNG) and the solitary autonomously functioning thyroid nodule

(AFTN). Preferential growth of actively secreting, TSH-independent thyroid follicles gives rise to palpable nodules. Although mostpatients remain euthyroid, some gradually develop biochemical, and later clinical, toxicity. The latter is more common with enlargingthyroid mass and advancing age, and in endemic goiter areas. The declining incidence of toxic goiters parallels the overall reductionin goiters, especially in endemic regions. AFTN and TMNG presently account for about 10% to 20% of all cases of hyperthyroidism.

Definitive therapy is indicated for frank toxicity, obstructive symptoms, and suspicion of malignancy. The choice between surgeryand radio iodine ablation should be individualized according to the general health and age of the patient, the severity of toxicity, the goitersize andpresence of obstruction, the possibility of malignancy, and prior treatment. Radioiodine ispreferredin patients who are medicallyunfit or elderly, especially if they have mild toxicity or a small gland, and in those who relapse after thyroidectomy. Despite the relativelyhigh dosages administered, hyperthyroidism may not be controlled for many months, and repeat applications are necessary in about aquarter of patients. Late hypothyroidism occurs quite commonly after radioiodine ablation of solitary AFTNs but less often after treatmentfor TMNG.

Subtotal thyroidectomy for TMNG and lobectomy for AFTN rapidly alleviate toxic symptoms and remove the goiter. It is most suitablein healthy and young individuals, those with obstructing goiters and possibly malignant nodules. Most patients are rendered euthyroidbut an increasing incidence of late hypothyroidism has been recognized following surgery for TMNG. Primary operations are very safebut higher complication rates attend reexplorations.

Nodular goiters that produce hyperthyroidism are broadlycategorized as toxic nodular goiters.' The term encompassesthe solitary autonomously functioning thyroid nodule (AFTN)(toxic adenoma) as well as toxic multinodular goiter (TMNG)(Plummer's disease). The pathogenesis, clinical presentationand treatment of these conditions differ from Graves disease:an autoimmune mechanism is hardly ever implicated; toxicitydevelops gradually over many years; patients tend to be older,and present more often with cardiac symptoms; exophthalmosis absent; nodules, either single or multiple, are characteristicfindings; and the radionuclide scan appearance seldom showsdiffuse uptake in both lobes.

PATHOGENESIS AND EVOLUTION OF NODULESToxic nodular goiter is not known to have an autoimmune

basis. Highly specific thyroid-stimulating immunoglobulin(TSI) is found almost exclusively in patients with Graves'disease (1). Reports of TSI in other hyperthyroid patients seemto represent Graves' disease co-existing with Hashimoto'sdisease (1) or a variant of TMNG (2). Toxic nodular goitershave TSH receptors and adenylate cyclase systems similar tothat in normal thyroid tissue (3). This implies a more distal

Room 1206, Melbourne Plaza, 33 Queen's Road Central, Hong KongJohn H. Boey, Dip. Am. Board of Surgery, private practiceCorrespondence to: Dr. John H. Boey

level of metabolic alteration whose cause and development isas yet unknown.

Nodule formation is a prominent feature of the condition.These apparently develop in response to intermittent TSHstimulation due to dietary iodine deficiency in endemic goiterregions, or to other growth factors, such as goitrogens, growth-stimulating immunoglobulins (4) or external radiation. Studerand colleagues (5,6) argue that there is a dissociation betweenfollicular replication and hormonal secretory function. Theypostulate that clones of cells with varying secretory abilitydevelop from different mother follicles. Preferential multiplica-tion of growth-prone daughter follicles gives rise initially topathologically demonstrable, and later clinically evident, nod-ules.

I-131 autoradiographic studies of surgical specimens byTaylor (7), Miller (8) and Studer (5,6) helped to elucidate theheterogeneous patterns of autonomous nodule development.Individual follicles may be scattered either haphazardlythroughout or clustered together within the gland (5). Somefollicles may combine to form microadenomas segregatedfrom the surrounding normal or hypofunctioning parenchyma,or progress to involve the entire thyroid. Combinations of thesebasic patterns may co-exist in different parts of TMNG. Mac-roscopic nodules evolve from polyclonal daughter follicles thatgrow within a confining lattice of fibrous scars produced byfollicular necrosis (6). Under a unifying hypothesis of toxicgoiters (6), the solitary AFTN, at one end of a broad spectrum,originates from a single clone of follicles that has supranormalsecretory as well as growth capacity.

166

Review Articles: Toxic Nodular Goiter

AUTONOMOUS ACTIVITY AND TOXICITYFunctional autonomy designates independence of follicu-

lar secretory activity from TSH regulation. This is character-ized by a radioisotope scan demonstrating increased uptake byone or more nodules that is not reduced (or may even berelatively enhanced) after TSH suppression by exogenousthyroxine. Following TSH stimulation, there is augmenteduptake in extranodular parenchyma, which may or may nothave been completely suppressed by thyroid hormone se-creted by the hyperfunctioning nodule (s). Not all hyperfunc-tioning nodules are autonomous. Some have normal or rela-tively low thyroid function, and may precede complete TSHautonomy (9,10).

Morphologically uniform areas may appear functionallyheterogeneous on radioisotope scanning. More sensitive thanscintigraphy, autoradiography can disclose follicles that possessactive iodine metabolism but appear "cold" on conventionalscans. A seemingly single AFTN may be surrounded by otherautonomous but metabolically less active follicles.

The unit hormonal secretory activity in autonomous nod-ules is quite variable, often subnormal (11,12), but usuallyremains stable even with increase in nodule size (13). Sincegrowth capacity and hormonal activity are dissociated in au-tonomous glands (8), large but poorly functioning multinodulargoiters may not manifest clinical or even biochemicalhyperthyroidism. Toxicity occurs when the product of themass of active follicles and their secretory activity exceedsnormal levels. A transitional phase of preclinical (or subclinical)hyperthyroidism can be identified by normal circulating hor-mone levels present in conjunction with a suppressed TSHlevel that is unresponsive to exogenous TRH stimulation(11,14,15). Preferential secretion of T3 over T4 under TSHstimulation may be reversed by propanolol leading to partialimprovement of the impaired TSH response to TRH (16).Selective resection of autonomous nodules in endemic goiterareas can re-establish a euthyroid state with full recovery ofTSH responsiveness to TRH (15,17).

The propensity of autonomous nodules to producehyperthyroidism varies according to the mass of autonomoustissue, which in turn varies with the age of the patient, numberof functioning nodules, and geographical area.

The risk of developing hyperthyroidism increases with thefunctioning mass (11,13,18). About two-thirds of nodulargoiters exceeding 75 grams in weight become autonomous(12). In sporadic TMNG, Jensen and his colleagues (19) foundthat 28% of their patients had resected gland weights below 50grams even though the average weight for their 442 patientswas 113 grams. In one endemic goiter area (11), the resectedspecimen weight averaged 48 grams in patients with nontoxicmultinodular goiter, 103 grams in those with preclinicalhyperthyroidism, and 130 grams in TMNG (11). A similarrelationship between size and toxicity holds true for AFTN.Among 48 patients with AFTN, euthyroid patients had smallernodules (mean area 5 cm2) than hyperthyroid patients (meanarea 8.9 cm2) (20). Based on planimetry measurements ofnodule size on scans, toxic nodules have a mass volume threetimes greater than nontoxic lesions (13, 21). In general, solitarynodules smaller than 2.5 cm hardly ever producehyperthyroidism whereas most lesions larger than 4 cm areeither toxic or completely suppress the extranodular thyroidtissue (22,23).

A gradual increase in goiter size accounts for the higherincidence of hyperthyroidism in elderly patients. Most studiesdocument a 12 to 16 years interval between the onset of a goiterand the development of clinical hyperthyroidism (18,19). Swiss

patients with nontoxic goiters had an average age of 45 years ascompared with 52 years in those with preclinicalhyperthyroidism, and 58 years in hyperthyroid patients withTMNG (11). Similarly, in Germany, goiters are common beforethe age of 40 but clinical toxicity more likely above 60 years(18). In sporadic goiter areas, there is a similar intervalbetween the development of a goiter and the onset ofhyperthyroidism (12).

In solitary AFTN, older patients tend to have larger nodulesand a greater risk of toxicity (21). In one large series (22),hyperthyroidism was present in 56.5% of patients 60 years orolder but in only 12.5% of those younger than 60 years. Somewhatunexpectedly, young individuals (under 20 years) did not havea higher proportion of toxicity than those between 20 and 60years of age (22). As pointed out by Thomas and co-workers(23), although functional activity in AFTN increases with age,it is not a strictly linear relationship. An inherent tendency ofmany AFTNs to undergo degenerative involution (10,21,24)lowers the expected incidence of toxicity in older individuals(22).

Endemic goiters are more apt to develop hyperthyroidismthan sporadic lesions. An estimated 50% to 60% of older patientswith autonomous nodules in endemic areas eventually develophyperthyroidism (25,26). Of the 93 patients operated upon forendemic goiters that contained autonomously functioningfollicles, only one-quarter had clinical hyperthyroidism (11).Sporadic autonomous goiters pursue a more indolent course:only six of 52 patients (11.5%) developed mild toxicity during afour years followup period (27).

Hyperthyroidism develops less frequently in solitary AFTNs(32%) than multinodular lesions (66%) in endemic areas (18). Ina collective series of 288 AFTNs, 96 (42%) were judged to behyperthyroid while another 21 (9%) had only biochemical(preclinical) hyperthyroidism (28). None of 48 euthyroidpatients with AFTNs became hyperthyroid during a two yearsfollowup period (28); in fact, nodule degeneration, occurred intwo of them. In Hamburger's extensive series (22), only 14 of142 (10%) euthyroid patients with AFTNs who were followedfor up to six years actually developed hyperthyroidism. De-pending upon the length of followup, the incidence ofhyperthyroidism among AFTNs ranged from 0% to 15%(10,21,24,28).

PATHOLOGYThyroid follicles in TMNG vary from medium to large in

size with epithelium composed of flat, low cuboidal cells. Bycontrast, the hyperactive follicles in a Graves' gland, consistingof high or columnar epithelium, are homogeneous and dif-fusely scattered throughout both lobes. A diffuse form ofTMNG can be distinguished from Graves' disease by thevariable follicular size, abundance of connective tissue andabsence of lymphocytic permeation (5). The solitary AFTN ischaracterized by a large encapsulated hyperactive folliclesurrounded by normal but suppressed parenchyma. Two-thirds of AFTNs are of the cellular microfollicular or simpleadenoma variety (24).

INCIDENCE OF TOXIC NODULAR GOITEROver the past several decades, the incidence of TMNG has

decreased dramatically in comparison with Graves' diseaseand AFTN. When Plummer at the Mayo Clinic first describedTMNG in 1913,it accounted for about 20% of their hyperthyroidcases. Paralleling the declining incidence of nontoxic goiters,only 59 cases of TMNG were treated at that same institutionbetween 1970 and 1974 compared with 334 cases between 1950

167

Journal of the Hong Kong Medical Association Vol. 42, No.3, 1990

and 1954 (19). In iodine-sufficient areas, TMNG now accountsfor about 4% to 15% of hyperthyroidism (29,30). In a recentsurvey of 201 hyperthyroid patients in New Zealand (31), 170had Graves' disease, 21 TMNG, and only 10 had AFTN. On theother hand, in iodine-deficient areas such as South America,Iran and parts of Europe (25), TMNG still accounts for up toone-half of hyperthyroid conditions. In a series of 630 surgicalpatients, the relative incidence of Graves' disease, TMNG andsolitary AFTN was 58.2%, 36.2% and 5.6% respectively (24). Thisepidemiological data supports the major promoting role ofiodine insufficiency and TSH stimulation in its pathogenesis,and suggests that the recent declining incidence of toxicgoiters in endemic areas is related to increased dietary iodineintake.

Solitary AFTN is seen inroughly 5% of patients with dominantsporadic nodules (22,32). However, most lesions are nontoxic,and Hamburger (22) encountered only one toxic AFTN forevery 50 Graves' lesions. In endemic goiter areas, toxic AFTNscan account for up to one third of hyperthyroid cases (18).

CLINICAL PRESENTATIONBecause a TMNG evolves from a preexisting nontoxic

goiter, sporadic TMNG, unlike other forms of hyperthyroidism,is more prevalent among patients in the seventh and laterdecades of life (19). Given the earlier onset of TMNG inendemic goiter areas, toxicity appears about a decade earlierbut still only after a 13 to 15 years period of evolution (18).Women are affected in about 80% of cases (19).

Unlike Graves' disease, hyperthyroidism in TMNG devel-ops insidiously. Seldom is the condition ushered in by adramatic flurry of thyrotoxic symptoms. Only after the diagnosisis made are mild toxic symptoms retrospectively ascribed tothis indolent condition. As sporadic cases occur mainly inelderly patients, cardiac symptoms (atrial fibrillation or con-gestive heart failure) predominate. Non-specific symptomssuch as weight loss, increasingly labile control of diabetesmellitus or delayed recovery from acute illnesses might raisethis diagnostic possibility to the astute physician. Less com-monly, impaired swallowing or stridor reflects tracheal com-pression by a large goiter or one in a retrosternal location.

Toxic AFTNs, although frequently existing by the fourthand fifth decades of life, usually become symptomatic only adecade later (19,22). Whereas the female to male sex ratio insporadic nontoxic autonomous nodules is about 14.9:1, a lowerratio of 5.9:1 is observed in toxic AFTNs (22). A largerproportion of men (33%) are affected (22), and this is even moreso in endemic regions (33). Most patients with AFTN areclinically and biochemically euthyroid (22,24), and a dominantnodule is often the sole finding (21,24). Tachycardia, anxietyand weight loss suggest the possibility of hyperthyroidism, andthe absence of a bilateral goiter and eye signs point to thecorrect diagnosis.

DIAGNOSTIC STUDIESInvestigations should detect hyperthyroidism, verify au-

tonomous function, and delineate the location, size and natureof the nodules. Relying on a single biochemical test will fail todiagnose hyperthyroidism in some cases. Screening testsshould include a serum RIA T4, T3 uptake and FTI. Accom-panying the gradual decrease in radioiodine uptake (RAIU) inthe general population, the 24 hours RAIU in TMNG hasdeclined simultaneously, from about 35% to 26% in one long-term study (19). The low sensitivity of RAIU in diagnosinghyperthyroidism is apparent given the finding that 22 of 35patients with large toxic goiters had a RAIU of less than 30%

(34). The RAIU is of value in estimating the radioiodine dosegiven for therapeutic ablation.

Autonomy of function is supported by the finding of anonsuppressible RAIU in conjunction with a positive TSHsuppression scan (after T3) (8). A TRH test is a sensitiveindicator of hyperthyroidism even in the preclinical stage. Ablunted TSH response with less than a 3 mU/L rise 30 minutesafter 200 micrograms of intravenous TRH (or 3 hours after 40mg TRH by mouth)is indicative of biochemical hyperthyroidism(11). More recently, supersensitive TSH that reliably measurescirculating TSH below 1 mU/L offers a convenient alternativeto the TRH test. It is suppressed below 0.3 mU/L in 97% ofhyperthyroid patients (35). Aserumfree T3 should be measuredin all patients suspected to have an AFTN because of a higherincidence (21,22) of T3 toxicosis with normal free T4 and FTIlevels (23,36), particularly in endemic goiter areas (33). TSHstimulation can lead to preferential secretion of T3 overT4 (36)but the serum T3 parallels the T4 level in most toxic patients(24). These more refined tests (high sensitivity TSH or TRHtest and free T3 levels) should be employed in patients whohave longstanding goiters and clinical hyperthyroidism.

Radionuclide imaging is helpful in diagnosing a solitaryAFTN when there is relative suppression of the extranodularparenchyma. After TSH stimulation (10IU), autonomy may beevidenced by a redistribution of isotope to previously sup-pressed areas (8) or by an increased RAIU. A repeat scan afterTSH suppression produces no diminution of uptake by anautonomously functioning hot nodule. Nonetheless, a scandoes not reliably distinguish between an AFTN and a hyper-functioning autonomous nodule within a TMNG. Cold areason a radionuclide scan may harbour hyperactive follicles thatcan only be visualised by autoradiography. This is partly dueto the limited sensitivity of radiographic photoemulsion films,and partly because a functioning area will still appear cold onscans if there is less than 9% relative uptake compared withadjacent hot areas (37). Hunter and Oakley (38) reported thatamong 22 patients with clinically solitary hot nodules, only ninehad solitary adenomas and ten had TMNG. Moreover, threeof six seemingly solitary autonomous nodules proved to behyperfunctioning nodules within a TMNG. Scans can help todifferentiate between TMNG and Graves' disease superimposedon a simple goiter because nodules in the latter fail to showisotope uptake (39).

Thoracic inlet x-rays that disclose retrosternal trachealcompression can alert the anaesthetist to a potentially difficultintubation. Ultrasonography provides supplementary infor-mation regarding the nature of an AFTN. A partially cysticmass, seen in as many as one-half of AFTNs, is more likely toundergo degeneration (24,28). Large, solid nodules shouldundergo fine needle aspiration biopsy to exclude a neoplasmthat requires surgical excision. However, false-positive errorsmay occur because of bizarre pleomorphic changes associatedwith AFTN (32).

INDICATIONS FOR DEFINITIVE TREATMENTFrank hyperthyroidism necessitating definitive treatment

develops in only a minority of patients with sporadic AFTN orTMNG. On the other hand, because euthyroid patients withendemic TMNG have a great risk of developing toxicity,surgeons in endemic areas are more liberal in advocatingsurgery. In two large studies, 56.7% and 74% of German andSwiss patients, respectively, underwent resection for onlypreclinical hyperthyroidism (11,18). This policy stems fromtheir young age of onset of disease, and the subsequentlylonger followup period with greater likelihood of developing

168

Review Articles: Toxic Nodular Goiter

hyperthyroidism. Treatment is generally advisable in healthypatients with a solitary AFTN larger than 3 cm in size (22),especially in older patients or those with evidence of preclinicalhyperthyroidism. Even though they may be biochemicallyeuthyroid, their disease is often rapidly progressive and symp-toms can be quite severe.

Tracheal obstruction can occur with huge TMNGs. In onestudy, ten of 13 TMNGs weighing 200 grams or more gave riseto tracheal compression, and seven of these were clinicallysymptomatic (40). Significant compression, more likely whenthere is a retrosternal component, is an indication for surgicaldecompression:

Malignancy arising in a hyperthyroid goiter is an uncom-mon but consistent finding in most surgical series. Thispossibility should be considered whenever there is a hard orenlarging dominant nodule within a longstanding goiter. Thereported incidence ranges from 2.6% (18) up to 10% (27) andseems to be higher in endemic goiter areas. Pacini and hiscolleagues (41) observed a 7.5% incidence of cancer in TMNGand 2.5% in AFTN. Although three of 29 patients (10.3%) withAFTN (including 24 with nontoxic disease) were found to havecoincidental thyroid cancer in another report (24), these weremerely occult papillary carcinoma. Other surgical series notea cancer incidence of between 4% (42) and 5.7% (24) in AFTNs.

Whether thyroxine suppression can avert definitive treat-ment in euthyroid patients with autonomous goiters is un-settled. TSH plays a role in the early development of nodules,and the adenylate cyclase system in hyperfunctioning nodulesresponds normally toTSH (3). Theoretically, TSH suppressionmight retard nodule growth or function in its early stages ofdevelopment. This is suggested by the observation that re-gression in nodule size occurred in 4 of 9 euthyroid patientswith AFTNs given thyroid hormone (23). Moreover, sup-pression of RAIU in solitary hot nodules was accompanied bya reduction in nodule size in 35% of 46 patients given thyroxin(9). However, because totally autonomous nodules are TSH-insensitive (6,11), it is arguable whether their continued growthwould be impeded by the withdrawal of TSH stimulus.Thyrotoxicosis may be induced inadvertently (12), and a TRHtest or high-sensitivity TSH level is advisable before prescrib-ing thyroxine.

SURGICAL TREATMENTSurgery can be performed on an elective basis in nearly all

cases. Antithyroid drugs alleviate toxic symptoms satisfacto-rily in all but a few elderly patients who present with acutecardiac failure. Attunes, surgery is feasible only after radioiodinehas been given because a patient is initially too ill forthyroidectomy (19). Antithyroid drugs may be dispensed within cases with only minimal hyperthyroidism (23).Preoperatively, propanolol is used besides antithyroid drugs.Iodine should be avoided because it can precipitate a Jod-Basedow form of thyrotoxicosis, particularly in iodine-deficientareas (21,37,43).

TMNGs are treated by subtotal thyroidectomy and solitaryAFTNs by unilobar thyroidectomy (32). Partial division of thestrap muscles improves the surgical exposure for largeTMNGs.Subcapasular dissection without lateral ligation of the inferiorthyroid arteries facilitates preservation of the blood supply tothe parathyroid glands. All macroscopic nodules should beexcised. Retrosternal gland extension can be dealt with bycarefully hugging the thyroid parenchyma and visualising therecurrent laryngeal nerves in order to deliver the lower compo-nent through the cervical incision. At times, the recurrentlaryngeal nerve may be more conveniently identified near its

insertion into the larynx after mobilisation of the upper pole,and subsequently traced caudad towards the larger lower polearea. Closed suction drainage is advisable because of the largeresidual dead-space. Despite even marked tracheal compres-sion, postoperative tracheal intubation is rarely needed.

Selective surgery of autonomous nodules has been prac-tised in endemic goiter areas (11,17). Between 6 and 20 gramsof non-nodular tissue, mostly in the upper poles, are left in situ.This policy resulted in an early reduction in the circulatingthyroid hormone level after surgery, and eventual recovery ofTRH responsiveness in 90% of patients (11,17).

As a result of the larger gland size and older patientpopulation, surgery for TMNG incurs a higher surgical mor-bidity than that for Graves'disease.Postoperative haemorrhageis encountered in roughly 1% of cases (18,19). Recurrentlaryngeal nerve paralysis develops in between 0.9% and 3.6%(11,18,19,44), especially in patients undergoing re-exploration(30) where is may be found in as much as one-fifth of patients(18). Hypoparathyroidism is permanent in about 1% of patients(19,30,44).

Hyperthyroidism is controlled in half of TMNG patientswithin six weeks, and in over three quarters of them within ayear of surgery (19). Serum T4 drops promptly after surgerybut only a minority of patients with overt or subclinicalhyperthyroidism achieve a normal TRH response within thefirst postoperative week (11). Full recovery of pituitary-thyroidfeedback control takes several weeks.

Hardly any patient with sporadic TMNG ever requires asecond treatment to alleviate hyperthyroidism (19). Persistenthyperthyroidism occurs occasionally in endemic TMNG (18).

Lobectomy for solitary AFTNs, incurring virtually nomortality or morbidity, eliminates hyperthyroidism in almostall patients (21,24).

RADIOIODINE TREATMENTBecause the relatively low RAIU of most TMNGs is offset

by the large size of most glands, a bigger ablative dose than thatused for Graves' disease is required. Most patients are given150 to 200 microCi per gram of estimated tissue (21,34,45).Other workers prefer a larger initial dose of 40 to 50 mCi forTMNG glands with an estimated weight between 100 and 200grams, and between 75 mCi and 100 mCi is used for very largegoiters or in markedly toxic patients (8,37). TSH may be givento increase the RAIU in glands that have alow RAIU or are smallin size. Antithyroid drugs are withheld until radioactive iodinehas been given. Hamburger (34) reported that a single cal-culated dose between 20 and 50 mCi was effective even forlarge goiters (200 grams or larger). In view of the variableresponse to calculated doses, and the observation that palpa-tion consistently underestimated the gland weight [by anaverage of 39 grams in one study (19)], some workers haveemployed a standard initial dose with considerable success. Of31 patients who had either TMNG or AFTN, only one requiredrepeat treatment after an initial 15 mCi standard dose (39). Asingle dose was effective in 78% of patients with large goiters(34).

I-131 treatment has theoretical appeal in treating solitaryAFTNs because the short-range beta particles emitted areavidly concentrated in the targeted hot nodule while sparingthe adjacent normal parenchyma. T3 or T4 is given pretreat-ment to minimize isotope uptake by the TSH-responsiveextranodular parenchyma (20). An effective dose of between10 and 15 mCi (corresponding to an administered dose ofbetween 30 and 45 mCi) of I-131 is needed to treat most AFTNsthat exceed 4 cm in size (37). Lugol's iodine is given after

169

Journal of the Hong Kong Medical Association Vol. 42, No. 3,

radioiodine ablation to retard damage to normal recoveringthyroid follicles (8,37). A single ablative dose proved effectivein most patients with solitary AFTNs (31,39) but four of 35 toxicAFTNs in one report (24) underwent surgery after failing torespond to initial radioiodine. Arapid uptake into a small iodinepool with a short turnover may lead to an insufficient exposureof the lesion to the radioiodine (24,37).

Hyperthyroidism tends to persist longer after radioiodineablation than after surgery (19). Only about 60% of TMNGpatients are no longer toxic within a year of radioiodine treat-ment (19). Large initial doses control hyperthyroidism morereliably and with a reduced need for a repeat dose. Neverthe-less, even 50 mCi was not effective after two months in a half ofpatients in one series (37). Occasional deaths [with eventhyroidstorm (51)] occurring before euthyroidism was achievedhave been reported after RAI but this is less common aftersurgery (37). This is probably due to radioablation beingselected for more critically ill, often hospitalized, patients (19).A repeat course of radioiodine, necessary in a quarter ofpatients, practically ensures successful control (19,31).

To avoid large doses of radioiodine, mostlarge TMNGs aretreated by surgery rather than I-131. The average gland weighsmore than 100 grams in surgical series (11,19) but in onlybetween 4% and 11% of radioablated patients (40). Althoughgland regression occurs in as many as one-third of TMNGpatients after radioiodine, this is usually modest, and a sizableresidual goiter is the rule (6). In one report (40), trachealcompression was reduced in five of seven patients with largeTMNG treated by radioiodine but only one derived relief ofobstructive symptoms, and one patient required surgery later.

After radioiodine treatment, only eight of 22 patients withAFTN in one series with long followup data had completeresolution of their nodules, and two even developed largerlesions (20). About half of these residual nodules were cold andthe rest were either warm or even hot on postoperative scans(20). Most patients rendered euthyroid after radioactive iodinehad persistent preferential isotope uptake in the nodule withsuppression of the extranodular tissue (21).

RECURRENCEThe major advantage of subtotal thyroidectomy for TMNG

is that not only is hyperthyroidism alleviated but the risk ofrecurrence is extremely low. Endemic AFTN or TMNG relapsedin between 0% (24) and 4.2% of patients (18) compared withnone after surgery in sporadic goiter areas (19). Because of thedissociation between follicular growth and function, destructionof only hyperfunctioning tissue by selective surgery orradioiodine treatment may not prevent recurrent goiter for-mation from hypofunctioning nodules (6). Six of seven goitersthat recurred after selective resection arose from macroscopi-cally normal lobes that were not resected (11). This supportsthe role of subtotal thyroidectomy in the operative managementof TMNG.

The value of thyroxine supplement to decrease the likeli-hood of relapse after thyroidectomy is unsettled. Thyroxinehas little to offer after resection of AFTN where the recurrencerate is less than 1% (8). Most recurrences in TMNG probablyarise from the proliferation of residual autonomous follicles.This is suggested by the observation that 10% of patients whowere euthyroid postoperatively had a persistently negativeTRH test (11). As such, not only would these patients not beexpected to respond to exogenous thyroxine but there is thepossibility of producing iatrogenic hyperthyroidism (11). Inendemic goiter areas, however, the iodine metabolism of theresidual TSH-dependent thyroid tissue may be impaired, andexogenous thyroxine supplement may abolish postoperative

goiter stimulation by a supranormal TSH level (11). Hence,thyroxine prophylaxis against postoperative recurrence maybe appropriate for goiters not giving rise to hyperthyroidism,particularly in endemic areas (11).

Apart from the one-quarter of patients who require a seconddose of radioiodine to alleviate hyperthyroidism, a small pro-portion relapse after initial control. Among 21 patients withTMNG, a cumulative 13% of patients relapsed within one to fiveyears after 20 mCi of radioiodine (31). An unexpectedly highproportion of patients (17%) relapsed two or more years afterreceiving 10 mCi for AFTN (31). The authors postulated thatthese cases might have been TMNG that were misdiagnosedas AFTN. Alternatively, these might have represented recur-rence in persistently functioning areas after radioiodine abla-tion (21).

IATE HYPGTHYROIDISMAfter subtotal thyroidectomy for sporadic TMNG, about

16% of patients become hypothyroid one year postoperatively(19). Although Simms and Talbot (29) reported a l2% incidenceof hypothyroidism after a mean followup of 5.8 years, othergroups note a much higher incidence of 50% (30) and even upto 70% (19) within five years of surgery. Hypothyroidismshould be expected in patients who undergo repeat treatmentby either surgery or radioiodine (19). A higher dietary iodinecontent (19) or more aggressive resection may account for therising incidence of hypothyroidism seen recently. Othersbelieve that the risk of late hypothyroidism is related to dif-ferences in the underlying pathology. Hypothyroidism devel-oped in 31% of patients with TMNG and diffuse hyperplasia(perhaps representing Graves' disease in a nodular goiter) butonly 3% of those with TMNG and nodular hyperplasia (46).

Hypothyroidism develops in between 16% (19) and 24% (31)of patients after radioiodine ablation of TMNG. Earlier seriesrecorded a lowerrate (47) but more recent reports (48) suggesta rising incidence that may be due to larger doses of radioiodinegiven or longer followup.

Permanent hypothyroidism develops in less than 10% ofpatients after lobectomy for solitary AFTN (21,30). A higherreported incidence can be ascribed to destruction of normalextranodular parenchyma by either prior radioiodine therapy(24) or subtotal thyroidectomy (49), or to an atrophic residuallobe (24). The normal lobe may take several months beforerecovering function so hypothyroidism should be consideredpermanent only if it persists beyond the first few months aftersurgery.

Reports of few or even no instance (21,45,50,51) of clinicalhypothyroidism among patients receiving about 10 mCi I-131for solitary AFTNs supported the notion that radioiodine couldselectively destroy the toxic lesion. However, Goldstein andHart (20) recorded a 36% incidence of hypothyroidism among22 patients followed an average of 8.5 years after receiving amean dose of 23 mCi. Danaci and co-workers (31) alsoreported a 40% cumulative rate of hypothyroidism within fiveyears of receiving an average dose of 12 mCi. Perhaps a lowerinitial dose might be equally effective without producing sucha high incidence of late hypothyroidism.

RECOMMENDED MANAGEMENTBoth radioiodine ablation and surgery offer effective de-

finitive treatment of toxic nodular goiter. The choice betweenthe two methods should be individualised according to thegeneral health and age of the patient, the severity of toxicity, thegoiter size and presence of obstruction, the possible risk ofmalignancy, and prior treatment.

Extreme safety and ease of administration makes radioiodine

170

Review Articles: Toxic Nodular Goiter

ablation appealing in medically unfit or very elderly individuals,especially if there is only mild toxicity or a small gland. A fixedinitial dose seems as suitable as a calculated dose based uponthe estimated weight and RAIU. A repeat dose should be givenif hyperthyroidism is not alleviated within six months. Becauseof the higher morbidity attending reoperations, recurrencesafter surgery are best treated by radioiodine.

Besides eradicating hyperthyroidism, surgery also removeswhat is usually a sizable gland with only a minimal risk of goiterrecurrence. Hence, operative management is optimal in oth-erwise healthy patients, especially if they are young or live in anendemic goiter area. Even elderly patients with marked tox-icity can be rapidly and predictably improved by surgery solong as their cardiac problems can be controlled beforethyroidectomy. Patients with obstructing lesions or a suspiciousnodule should be regarded in the same manner as those withnontoxic goiters and undergo operation.

Solitary toxic AFTNs are also best treated by a lobectomy.It is extremely safe, spares the normal thyroid parenchymathereby achieving a high rate of euthyroidism, and avoids alarge dose of radioiodine that is attended by a high incidenceof late hypothyroidism.

Thyroxine need not be given routinely after definitivetherapy, especially after lobectomy for AFTN. It may benecessary after subtotal thyroidectomy for TMNG if serumTSH levels are raised. Lifelong followup is essential even afterinitially successful treatment. Periodic thyroid function testsare needed to detect late-onset hypothyroidism and to adjustthyroxine replacement doses.

REFERENCES1. Rappaport B. Greenspan FS, Filetti S and Pepitone M. Clinical experience with a

human thyroid cell bioassay for thyroid-stimulating immunoglobin. J Clin EndocrinolMetab 1984; 58:332-338.

2. Kraiem Z, Glaser B, Yigla M, Pauker J, Sadel O and Sheinfeld M. Toxic multinodulargoiter a variant of autoimmune hyperthyroidism. J Clin Endocrinol Metab 1987;65:659-664.

3. Thomas CG Jr. Combest W, McQuade R, Jordan H. Reddick R and Nayfeh SN.Biological characteristics of adenomatous nodules, adenomas, and hyperfunctioningnodules as defined by adenylate cyclase activity and TSH receptors. World J Surg1984; 8:445-451.

4. Smyth PPA, Neylan D and O'Donovan DK. The prevalence of thyroid-stimulatingantibodies in goitrous disease assessed by bytochemical section bioassay. J ClinEndocrinol Metab 1982; 54:357-361.

5. Studer H, Hunziker HR and Ruchti C. Morphologic and functional substrate ofthyrotoxicosis caused by nodular goiters. Am J Med 1978; 65:227-234.

6. Studer H, Peter HJ and Gerber H. Toxic nodular goitre. Clin Endocrinol Metabol1985; 14:351-372.

7. Taylor S. The evolution of nodular goiter. J Clin Endocrinol 1953; 13:1232/-1241.8. Miller JM. Hyperthyroidism from the thyroid follicle with autonomous function.

Clin Endocrinol Metab 1978; 7:177-197.9. Greene R and Farran HEA. On single "hot" nodules of the thyroid gland. J

Endocrinol 1965; 33:537-538.10. Silverstein GE. Burke G and Cogan R. The natural history of the autonomous

hyperfunctioning thyroid nodule. Ann Intern Med 1976; 67:539-548.11. Gemsenjager E, Heitz PU, Staub JJ, Girard J, Barthe P and Benz UF. Surgical

aspects of thyroid autonomy in multinodular goitre. World J Surg 1984; 7:363-371.12. Miller JM and Block MA. Functional autonomy in mullinodular goiter. JAMA 1970;

214:535-539.13. Demeester-Mirkine N and Ermans AM. Euthyroid "hot" nodules: a physiological

approach. In: Irvine WJ (ed). Thyrotoxicosis. Edinburgh E and S Livingstone 1967;68-75.

14. Ridgway EC, Weintraub BD, Cevallos JL, Rack MC and Maloof F. Suppression ofpituitary TSH secretion in the patient with a hyperfunctioning thyroid nodule. J C!inInvest 1973; 52:2783-2792.

15. Gemsenjager E, Staub JJ, Girard J and Heitz PH. Preclinical hyperthyroidism inmultinodular goiter. J Clin Endocrinol Metab 1976; 43:810-816.

16. Elte JWF, Haak A, Wiarda KS, et al. Popranolol improves the impaired TSHresponse to TRH in patients with autonomously functioning euthyroid multinodulargoitre. Clin Endocrinol 1982; 16:553-563.

17. Blichert-Toft M. Christiansen C, Axlesson CK, Egedorf J, Ibsen H and Ibsen J.Effect of selective goitre resection on absent thyrotropin response to thyrotropinreleasing hormone in idiopathic euthyroid goitres. Clin Endocrinol 1978; 8:95-100.

18. Goretzki PE, Wahl RA, Branscheid MD, Joseph K, Tsuchiya A and Roher HD.Indication for operation of patients with autonomously functioning thyroid tissue inendemic goiter areas. World J Surg 1985; 9:149-155.

19. Jensen MD, Gharib H, Naessens JM,van Heerden JA and Mayberry WE. Treatmentof toxic multinodular goiter: surgery or radioiodine? World J Surg 1986; 10:673-680.

20. Goldstein R and Hart IR. Follow-up of solitary autonomous thyroid nodules treatedwith I-131. N Engl J Med 1983; 309:1473-1476.

21. Blum M, Shenkman L and Hollander CS. The autonomous nodule of the thyroid:correlation of patient age, nodule size and functional status. Am J Med Sci 1975;269:43-50.

22. Hamburger JI. Evolution of toxicity in solitary nontoxic autonomously functioningthyroid nodules. J Clin Endocrinol Metab.1980; 50:1089-1093.

23. Thomas CG Jr. Tawil M, Berman MI and Nayfeh SN. TSH suppression in themanagement of autonomously functioning thyroid lesions. World J Surg 1986;10:797-802.

24. Bransom CJ, Talbot CH, Henry L and Elemenoglou J. Solitary toxic adenoma of thethyroid gland. Br J Surg 1979; 66:590-595.

25. Emrich D and Bahre M. Autonomy in euthyroid goitre: maladaptation to iodinedeficiency. Clin Endocrinol 1978; 8:257-265.

26. Ermans AM and Camus M. Modifications of thyroid function induced by chronicadministration of iodide in the presence of "autonomous" thyroid tissue. ActaEndocrinol 1972; 70:463-475.

27. Wiener JD and DeVrics AA. On the natural history of Plummer's disease. Clin NuclMed 1979; 4:181-190.

28. Burman KD, Earll JM, Johnson MC and Wartofsky L. Clinical observations on thesolitary autonomous thyroid nodule. Arch Intern Med 1974; 134:915-919.

29. Simms JM and Talbot CH. Surgery for thyrotoxicosis. Br J Surg 1983; 70:581-583.30. Heimann P and Martinson J. Surgical treatment of thyrotoxicosis: results of 272

operations with special reference to preoperative treatment with anti-thyroid drugsand L-thyroxin. Br J Surg 1975; 62:683-688.

31. Danaci M. Feek CM. Notghi A, Merrick MV, Padfield PL and Edwards CRW. I-131radioiodine therapy for hyperthyroidism in patients with Graves' disease. uninodulargoitre and multinodular goitre. NZ Med J 1988; 101:784-786.

32. Thomas CG Jr. Croom RD III. Current management of the patient with autonomouslyfunctioning nodular goiter. Surg Clin North Am 1987; 67:315-328.

33. Safa AM and Nakhjavani MK. Autonomously functioning thyroid nodule. CleveClin J Med 1988; 55:227-230.

34. Hamburger JI and Hamburger SW. Diagnosis and management of large toxicmultinodular goiters. J Nucl Med 1985:26:888-892.

35. Bayer MF, Kriss JP and McDougall IR. Clinical experience with sensitive thyrotropinmeasurements: diagnosticand therapeutic implications. J Nucl Med 1985; 26:1248-1252.

36. Carpi A, Bianchi R, Zucchelli GC, Del Corso L, Levanti C, Cocci F, Giannessi D andMariani G. Effect of endogenous thyroid stimulating hormone levels on thesecretion of thyroid hormones in man. Acta Endocrinol 1979; 92:73-84.

37. Miller JM. Plummer's disease. Med Clin North Am 1975; 59:1203-1215.38. Hunter R and Oakley JR. Hot nodules of the thyroid gland. Aust NZJ Surg 1975;

45:191-196.39. NG SCTF and Maisey MN. Standard dose therapy for hyperthyroidism caused by

autonomously functioning thyroid nodules. Clin Endocrinol 1979; 10:69-77.40. Hamburger JI, Kadian G and Rossin HW. Why not radioiodine therapy for toxic

nodular goiter. Arch Intern Med 1967; 119:75-79.41. Pacini F. Elisei R, Di Coscio GC, Anelli S, Macchia E, Concetti R, Miccoli P, Arganini

M and Pinchera A. Thyroid carcinoma in thyrotoxic patients treated by surgery. JEndocrinol Invest 1988; 11:107-114.

42. Johnston IDA. The surgery of thyroid cancer. BrJ Surg 1975; 62:765-770.43. Livadas DP, Koutras DA, Souvatzoglou A and Beckers C. The toxic effects of small

iodine supplements in patients with autonomous thyroid nodules. Clin Endocrinol1977; 7:121-127.

44. Palestini N, Valori MR, Carlin R and lannucci P. Mortality, morbidity and long-termresults in surgically treated hyperthyroid patients. Acta Chir Scand 1985; 151:509-513.

45. Bliddal H, Hansen JM, Rogowski P, Johansen K, Friis T and Siersbaek-Nielsen K.Treatment of diffuse and nodular toxic goitre with or without antithyroid agents.Acta Endocrinol 1982; 99:517-521.

46. Lundstrom B and Norrby K. Thyroid morphology and function after subtotalresection for hyperthyroidism. Br J Surg 1980; 67:357-359.

47. Eller M, Silver S, Yohalem SB and Segal RL. The treatment of toxic nodular goitrewith radioactive iodine: 10 years experience with 436 cases. Ann Intern Med 1960;52:976-1013.

48. Holm LE, Lundell G, Israelsson A and Dahlqvist I. Incidence of hypothyroidismoccurring long after iodine-131 therapy for hyperthyroidism. J Nucl Med 1982;23:103-107.

49. Molnar GD, Wilber RD, Lee RE, et al. On the hyperfunctioning thyroid nodule.Mayo Clin Porc 1965; 40:665-684.

50. Ross DS, Ridgway EC and Daniels GH. Successful treatment of solitary toxicthyroid nodules with relatively low dose iodine-131 with low prevalence ofhypothyroidism. Ann Intern Med 1984; 101:488-490.

51. Ratcliffe GE, Cooke, Fogelman I and Maisey MN. Radioiodine treatment of solitaryfunctioning thyroid nodules. Br J Radio 1986; 59:385-387.

171