Thyrotoxicosis is defined as the situation in which increased levels of thyroid hormone in the serum lead to biochemical and/or clinical

signs of excess thyroid hormone at the tissue level. In other words, the mere presence of increased levels of total and free thyroid hormone is not sufficient for the diagnosis of thyrotoxicosis. For instance, in resistance to thyroid hormone, increased thyroid hormone levels are found while euthyroidism or sometimes even hypothyroidism is present (see Chapter !". Increased serum levels of thyroid hormone leading to thyrotoxicosis, may result from overproduction of thyroid hormone (termed hyperthyroidism" or lea#age of stored iodothyronines due to thyroid gland damage, but may also be caused by unintentional or deliberate over$ingestion of thyroid hormone. % very common cause of thyrotoxicosis is hyperthyroid &raves' disease, described in Chapter (. In this chapter we describe a variety of other causes of thyrotoxicosis.

% toxic adenoma (T%" of the thyroid is an autonomously functioning thyroid nodule (%FT)" that produces supraphysiological amounts of thyroid hormone leading to increased serum levels of T* and/or T+ and suppression of serum T,-. The normal thyroid tissue that surrounds the nodule is often atrophic when autonomy is longstanding.

In the last decade much information has been accumulated about the pathogenesis of T% at the genetic level. Two different types have been described. % somatic mutation in the gene for the alpha polypeptide of the & protein (&s alpha" resulting in inhibition of &T.ase activity, and a somatic mutation in the T,-$receptor (T,-$/" gene, both leading to constitutive activation of adenylate cyclase (C%" activity and to autonomous hyperfunctioning thyroid adenomas. The ma0ority are mutations in the T,- receptor ( 1" %n analysis of ** T% from * patients for the presence of somatic mutations in the T,-$ / gene disclosed in (2 T% (3(4", activating mutations at ( different residues or locations. These mutations cause low$level chronic activation of the T,-$/ independent of T,- levels. In addition, in ( T% (!4", mutations were detected in the &s alpha gene. 5nly in four T% were no mutations observed ( 1a". This study thus shows that in the ma0ority of 6elgian patients T% are caused by mutations of the gene of the T,-$/. In a study from 7apan, investigating mutations in the T,-$/ gene in the 8hot spots8, i.e. coding for the third cytoplasmic loop and the sixth transmembrane segment, a mutation was found only in /*3 %FT). This mutation however did not display any functional abnormality ( 1b". % study from %ustria analy9ing the same hot spots reported a fre:uency of * out of (2 %FT) ( 34", with mutations in these areas ( 1c". )o mutations in the gene of the T,-$/ or &s$alpha were detected in ; toxic thyroid adenomas in an Italian study,( 1ca", but in six out of seven %FT) in 6ra9ilian patients, mutations were detected in the T,-$/ ( 1ca ". <evels of stimulatory and inhibitory & protein$alpha subunits were studied in toxic adenoma with or without T,-$/ gene mutations together with basal and T,-$stimulated C% activities. =xpression of both protein subunits was increased independent of the presence or absence of T,-$/ gene mutations. %lso no correlation was present between basal and T,-$stimulated C% activity and &s protein

subunit levels.( 1cb" The authors concluded that mutational activation of the c%>. cascade is not sufficient to generate toxic adenoma and that the pathogenesis of %FT) is probably much more complex. Furthermore it was shown that C% concentrations in %FT) with mutant or wildtype T,-$/ or &s alpha were not different, but that total phosphodiesterase (.?=" activity was higher in the mutant %FT)'s, primarily due to induction of .?=+?. This intracellular feedbac# mechanism may have an impact on the phenotypic expression of mutant %FT)'s ( 1cb ". ?erwahl ( 1f" states that, in addition to mutational changes in the genes of the T,-$/ and &s alpha protein causing T%, the natural heterogeneity of thyrocytes responding to these mutations may play a role in the phenotype expression. This heterogeneity may affect the degree of (hyper" function and histomorphology in the sense of monoclonal or polyclonal proliferation. ?espite different results in the early years it is now recogni9ed that constitutively activating T,- receptor mutations, and with a lower prevalence, mutations of the &s$ alpha, play a principal role in the pathogenesis %FT) ( 1" For those monoclonal T% where no mutations are found in the T,-$/ or &s$alpha unit, probably other somatic mutations are involved ( 1fc". %lthough some believe that iodine deficiency may increase mutation rate and functional expression of autonomy ( 1 fa" in %FT), others ( 1fb" consider the fundamental process of goitrogenesis in (multi"nodular goiter as independent from I? but operating through mechanisms innate to the hereditary and ac:uired heterogeneity among the thyrocytes themselves. -owever,superimposed iodine deficiency may shift clinical expression to younger ages. @an ,ande et al ( 1d", hypothesi9ed that, as ! different activating mutations were identified in the T,-$/ gene, that this receptor is in a constrained conformation in its wild$type form. They sub0ected C-5$A cells or C5,$2 cells transfected with the human T,- receptor, to mild trypsin treatment, and observed increased cyclic %>. formation. The effect was also observed with the dog T,- receptor, but not with the >,- or <- receptor. The action of trypsin removes or destroys residues *;+$*;B of the extra cellular domain of the T,-$/. The results of their study support the hypothesis that the C$terminal portion of the large extracellular domain plays a role in the maintenance of this constraint. Further studies from the same group indicated that the first and second extracellular loops contribute to the silencing of the unliganded receptor. This study also showed that both the cyclic %>. and the inositol$phosphates pathways may be activated by T,-$/ gene mutations. These mutations are distributed over the first and second extracellular loops, the third intracellular loop, and the third, sixth and seventh transmembrane segments 1e. They also report that T% have a high level of )aC/iodide symporter gene expression, a high thyroperoxidase m/)% and protein content, and a low -(5( generation. Inositol upta#e was also increased but inositolphosphates were not increased. T% secreted more thyroid hormone than the :uiescent surrounding tissue. 5ther characteristics of T% were, increased cycling of thyrocytes as compared to normal surrounding tissue, little apoptosis, and low expression of early immediate genes ( 1ea". %n important study by Fuhrer et al ( 1eb" shows that a panel of different activating T,-/ mutations cause different functional and morphological responses in vitro in rat and human primary thyrocytes. Their data suggest that different biological properties of the T,-/ mutants may result in different in vivo phenotypes( 1ec"

The prefix 8toxic8 defines the adenoma from the functional point of view. It is clinically and scintigraphically a single nodule in combination with biochemical changes and clinical signs of thyroid hormone overproduction. 6efore the availability of sensitive diagnostic tests, particularly the sensitive T,- assay, it was often necessary to establish the diagnosis of a toxic nodule by administration of T* or T+. Dpta#e of radioactive iodide or pertechnetate in the nodule would not be suppressed by this maneuver. In addition, administration of exogenous T,- could cause upta#e of isotope in the surrounding previously suppressed thyroid tissue. )owadays the presence of elevated serum free T+ and T* levels, and suppressed serum T,-, in combination with radionuclide upta#e only in the nodule on scintiscan, ( Fig. *$ "is sufficient for the diagnosis. -yperfunction of a remnant of thyroid tissue, for instance after thyroidectomy or after thyroiditis, is not excluded by these tests but is very rare. To discriminate between these two possibilities, the presence of a thyroidectomy scar, careful history ta#ing, and measurement of circulating thyroid autoantibodies may be helpful. Figure 1. Hot nodule in right lobe of th roid. Note that u!ta"e of radioa#ti$it in the #ontralateral lobe is su!!ressed.

+" E!ide%iolog %pproximately in suppressed and there is typically no activity visible on the scan outside the nodule. ( *. * Forty$eight percent of euthyroid sub0ects were +1 years or older.!4 were toxic. In the remaining *! patients with larger nodules.. 5f the (!! patients who were younger than +1 years only B. whereas this was the case only in *4 of patients younger than !1 years. The difference between a 8hot8 and a 8toxic8 nodule is that in the latter T. Fre&uen# of To'i# Adeno%a in (arious Countries )o#ation Period No. cm in diameter and of these only .4 had nodules * cm in diameter or larger. have been reported (see Table *$ ". whereas 2*4 of hyperthyroid patients fell in this age group. Table still in the normal range and extranodular thyroid tissue is visible on the thyroid scan. but only 24 in females. ( *. times more common in women than men. *d+ 0i' ears after bread iodination.The functional development of a toxic adenoma of the thyroid is from a 8warm8 nodule via a 8hot8 nodule to a 8toxic8 nodule.. The proportion of cases of %FT) with hyperthyroidism was **4 in males.%./ ears of age. whereas a 8hot8 nodule has more activity than the surrounding tissue.. The fre:uency of toxic adenoma in patients referred for thyrotoxicosis may vary considerably in different geographical areas.B4 were toxic. cm in diameter are rarely toxic. *b+ Th roto'i#osis sub%itted to surger . In =urope a female to male ratio of . % warm nodule is defined as a nodule that cannot scintigraphically be distinguished from the normal surrounding thyroidal tissue. In a group of *+B patients with autonomous functioning thyroid nodules (%FT)" -amburger found 34 to be toxic. whereas in the older patients this figure was +. *Fro% Orgia11i2 *31+ 4ith !er%ission. 5f the group of patients !1 years or older.+ Europe %ustria B!!$ B!3 3( ++.E was reported for toxic autonomous nodules ( !".. Two$hundred$thirteen patients had nodules up to (. being more common in =urope than in the D. to in (1 solitary nodules present with hyperthyroidism.ercentages between .. This varies from country to country.. % nodule that is 8hot8 on scintiscan may not actually overproduce hormone in which case serum T.24 were toxic... . of Th roto'i# Patients Per#ent of To'i# Adeno%as *a+ . *#+ Patients under . ."The problem is .B4. and ++. . +(.disease !lus to'i# adeno%as. These data underline the fact that larger %FT) occur in the older age group and that at the time of presentation. nodules less than (. It is unusual that an autonomously functioning thyroid nodule is toxic when the diameter is less than * cm. .ra$es..

*2 (+1 *. *..$ B!2 B!.1 !3! . $$ ( .2 B. B! $ B2B (.+* (b" .outhfield >I Australia Period B+3 B!B No.urvey North America Cleveland )ew For# /ochester /ochester . ( $$ B(+ ** (+ . . B!3 B!3 B!2 B3! (+ . (*.)o#ation =ngland Finland France .3+!(a" (.B .+$ B!.aris >arseille >ontpellier &ermany &reece Italy .!(2 ( ..wit9erland &eneral .2 B.3 .2 3 Per#ent of To'i# Adeno%as B!( B!+ B!.! .+ (2.. of Th roto'i# Patients 12 (.B(c" B!( B++ B ( B.

3 per 11. Changes in nodule si9e as observed in . secondary ac:uisition of new inheritable :ualities by replicating cells. but is much more common in nodules over * cm in diameter (up to (14" ( *". below". ( . *$(". >icroscopically one would expect. Thus it is :uite possible that. =ight percent developed overt thyrotoxicosis in a mean follow$up of * to . as in multinodular goiter (see Ch. years ( *" are shown in Table *$(. of Th roto'i# Patients 33 2 Per#ent of To'i# Adeno%as % study from >almG compared the mean annual incidence of T% between B33 and BB1 (+. This finding is in agreement with the thesis of . Toxicity may develop independent of age. it is apparent that also in the isolated toxic adenoma multifunctional follicles appear to be present (Fig.tuder et al. to see the picture of a true adenoma with uniform thyroid follicles and without characteristics of malignancy. may also be present in toxic adenomas. In one series 14 of patients followed for ! years became toxic. %n increase in si9e was seen in only 14. Patholog 5n macroscopic examination.111" with that between B21 and B2+. . Three percent developed borderline hyperthyroidism (Table *$*". a solitary toxic nodule is surrounded by normal thyroid tissue that is functionally suppressed.tuder et al. autonomously functioning micronodules are seen in the extranodular tissue. renders the function and the histological picture of the follicles heterogeneous. sometimes reflected by calcification. grow. but usually are composed of heterogeneous follicles of different si9es and different capacity to ta#e up radioactive iodine (Fig.B patients followed between $ . appear occasionally to be monoclonal in function ( as has also been shown to be the case on the basis of somatic point mutations in the T. 6y sonography the critical volume at which hyperthyroidism will occur. )o difference in incidence was found ( !a" Natural histor %utonomously functioning nodules may stay the same si9e. 5n microscopic examination of a thyroid with a clinically single toxic adenoma. Four percent decreased in si9e. 2".("found that hot nodules in so$called multinodular goiter. *$*.)o#ation Tasmania Period B2* (d" No. %lthough such heterogeneity has been identified in multinodular goiters. degenerate or become gradually toxic.-$/ gene (see Chapt. 5ld hemorrhage. <oss of function was seen in + patients because of degeneration. years. 2". on the basis of current ideas about pathogenesis. ( . although of monoclonal origin. was ! ml( 2". This multifocal histological picture however should not a priori be interpreted as suggestive of heterogeneous origin.(" that the true adenoma is one end of a large spectrum of thyroid nodules growing from single follicular cells or tiny cell families each replicating with an .

individual growth rate. Autoradiogra!h of a hot nodule illustrating areas 4ith different #a!a#it of u!ta"e of radioa#ti$e iodine *ta"en fro% ref. 52 4ith !er%ission+. 7nifor% nature of #ells in a nodule for%ed b !roliferation of onl one or a fe4 #lones of e!ithelial #ells *ta"en fro% ref. whereas the grossly abnormal multinodular goiter is situated at the other end of the scale. 12 4ith !er%ission+. Figure 5. Figure 6. .

. The symptoms of thyrotoxicosis are not different from those with other causes of thyrotoxicosis except that characteristics of &raves' disease.Clini#al !resentation .atients with toxic adenoma tend to be older than those with &raves' disease and onset of thyrotoxicosis is generally slow. Coincidental occurrence of the two diseases may be seen ( 3". are not present. )odules hardly ever are of such si9e that mechanical symptoms are present other than a slight discomfort during swallowing. obviously being non$toxic for a long time. .atients sometimes visit their doctor with cosmetic reasons as the primary complaint. Correlation of Change in Nodule 0i1e and Duration of Follo48u! for Nonto'i# AFTN Patients .atients with toxic adenomas present with a lump in the nec# with/or without symptoms compatible with thyrotoxicosis. pretibial myxedema and acropachy. >any patients are aware of having a lump in the nec# for some years. Table 5. such as ophthalmic disease.

+. degeneration )o change. =esults of Follo48u! of 7ntreated Patients 4ith Nonto'i# AFTN Duration of Follo487! * r+ Author Countr >ear No. transient toxicity. euthyroid. euthyroid C cm or more.81.B + 1 1 1 1 1 .+ C cm or more and became toxic C cm or more. 1 + B ( (( Table 6. degeneration )o change )o change.Duration of Follo487! * r+ Change in Nodule 0i1e 185 689 ....$3. toxic $ cm or more C cm. of ?orderline =ange Mean H !erth roid Patients H !erth roid *Fro% Ha%burger2 *16+ 4ith !er%ission.3 1 .. *a+ One additional !atient !resented 4ith a#ute nodular enlarge%ent and T6 to'i#osis2 both of 4hi#h subsides s!ontaneousl .+ >cCormac# D.8: . then $ cm Total ((a" 2B 1 +( !1 * . *Fro% Ha%burder2 *16+ 4ith !er%ission. B!2 + (. ( + * 1 *2 1 * * 1 ( 1 2 + 1 1 ! ( . Total <2 Nodule in#reased in si1e2 82 nodule de#reased in si1e.

.. .ilverstein >iller 6urman 6lum Countr D. %s Tc5+$ is not organified in thyroid tissue (in contrast to radioactive iodine".. of ?orderline =ange Mean H !erth roid Patients H !erth roid B . ($2 $2 /*$ . B2.value theoretically is sufficient to establish the diagnosis of a toxic nodule. measurement of a serum (free" T+ (and when normal of serum (free" T*" is important. The scan of a toxic nodule will show prominent upta#e in the nodule with little or no upta#e in surrounding thyroid tissue... -owever. . *$+" /are nodules may be hot with Tc5+$... if T. -amburger D. and will show appreciably less upta#e in the surrounding tissue in the case of a hot nodule. >ear B!2 B!3 B2+ B2. . to ascertain the severity of thyroid overactivity. No. indicating hyperthyroidism.3 + ! *. D. D. the finding of a suppressed serum T. ... <obo Ieiner 6ra9il Current .. D.B B!.* *.... It is wise to obtain a thyroid scan.. This is not necessary however. while being cold on scanning using radioactive iodine. the scan should be repeated using I (* ( B". discrepancies are occasionally seen.Duration of Follo487! * r+ Author . In these situations the nodule should be considered cold and therefore of malignant potential.3 )etherlands B2B )aborator diagnosis Ihen clinical symptoms of thyrotoxicosis are evident and a single nodule within the thyroid area is clearly felt with little surrounding tissue on either side. /($* $ . +3 * H $ ( $ . preferably using (*$I. It is therefore advised that if a nodule shows prominent activity with suppressed.* + * ( 1 1 1 + 1 + 1 ( 1 1 1 ! -amburger D.. (Fig.

this is virtually never re:uired to establish the diagnosis. Ihen a hot nodule is present. if not impossible. The presence of carcinoma in a toxic or hot nodule is rare..((" % study from the Dnited . (( . Treat%ent . Isolated cases of carcinoma development in a hot nodule have however been reported. autonomous function of the nodule can be proven by administration of T+ ((11 ug/day for + days". . This can lead to a high proportion of false positive cytological diagnoses of follicular carcinoma. Dltrasound will often reveal a small contralateral thyroid lobe as well as the dominant nodule. -orst et al.-. ((+" It is generally felt that the presence of autonomous function is a reassuring characteristic with regard to the possible presence of thyroid carcinoma. In a thyrotoxic patient with a solitary hot thyroid nodule in which the surrounding tissue is devoid of substantial upta#e.tates ((*" reported the occurrence of * carcinomas in *1 consecutive patients operated for solitary hot nodules. It is of little use to perform fine needle aspiration in patients with toxic nodules because cytopathologic differentiation between adenoma and thyroid carcinoma is difficult. ((1" reviewed the literature on occurrence of carcinoma in a solitary hyperfunctioning nodule. after previous thyroidectomy or in thyroid dysgenesis" is within normal limits. Nodule in isth%us of the th roid 4hi#h is @hot@ on the sodiu% !erte#hnetate T# AA% s#an *left+ and @#old@ on the I161 s#an *right+. ( !" found no thyroid malignancy in a study of *1! patients with %FT). They also concluded that the incidence of malignancy in a hot thyroid nodule is exceedingly low.Figure 9. (-owever some authors suggest that occurrence of carcinoma in %FT) may be more than coincidental.ander et al.and subse:uent scanning of the thyroid. %fter this a repeat thyroid scan should show that the surrounding tissue is inactive because of suppression of serum T. -owever. but there is still (be it less" upta#e of isotope in surrounding tissue and serum T.. this procedure has no practical conse:uences and is therefore unnecessary in clinical practice. The ultimate proof that surrounding tissue is suppressed but present can only be obtained after administration of r$T. but again adds little to the evaluation. the possibility of the presence of &raves' disease in remnant thyroid tissue (e. -owever.

Three definitive forms of treatment are available. treatment with radioactive iodine and percutaneous ethanol in0ection into the nodule. In another series of patients..e. The incidence of hypothyroidism after operation is low.". The disadvantages of surgery are the ris#s of general surgery and the expense as well as the residual scar.". if mild thyrotoxicosis is present. There are advantages and disadvantages to these approaches. It seems li#ely that coexistence of another thyroid disease was the culprit. probably due to a hemorrhage in the adenoma. i. Th roid s#an before *left+ and after *right+ nodule#to% . The advantages of nodulectomy are rapid and permanent control of hyperthyroidism with a very low operative complication rate. Figure .. )o information however is available about the presence of circulating thyroid autoantibodies and macroscopic status of the contralateral lobe in these cases ( . *$.".measurements at intervals of ! to ( months are usually sufficient. but surprisingly not 9ero. <ong$term treatment of a toxic nodule with antithyroid drugs is useless. There are anecdotal observations that sometimes. nodulectomy. also treated surgically by unilateral lobectomy for toxic adenoma. . . Dsually the patient is treated preoperatively by antithyroid drugs or.%s discussed in the previous section. In the case of a hot nodule no active treatment is necessary. out of *. spontaneous resolution of the nodule occurs or the nodule becomes cold on scan. as relapse will almost invariably occur after discontinuation of medication. by beta$bloc#ing agents. Those nodules that grow in si9e and/or lead to overt thyrotoxicosis should be treated since thyrotoxicosis is generally permanent. The ma0ority of patients remain euthyroid. though in * it was only temporary. Thus. It is difficult to see how patients become permanently hypothyroid even after hemilobectomy. &enerally it is believed that long$term suppression of the thyroid gland does not lead to permanent inactivation after suppression is relieved (Fig. became hypothyroid. the occurrence of malignancy in a hot or toxic nodule is rare. Clinical observation and serum T. in a series of !1 patients operated for autonomously functioning thyroid nodules( +". Two of these patients had received in the past either therapeutic doses of * I or long term treatment with antithyroid drugs ((.!4 became hypothyroid after operation. !.

the level of thyroid function at therapy. and therefore is damaged by the isotope. %lso at the same time after therapy. or the total amount of administered radioactivity. It is also possible that high doses of * I in the nodule provide enough radiation to the surrounding tissue that its function is seriously damaged.. 1 years after * $I treatment. hypothyroidism may be documented. The incidence of hypothyroidism was not related to nodule si9e.+4 of patients nodules were still palpable. and in only . Ihen antithyroglobulin and/or antithyroid microsomal antibodies were present. years after treatment. In a similar study ((B". prior to * $I treatment to be sure that the normal surrounding thyroid tissue is suppressed. The prevalence of hypothyroidism after treatment with radioactive iodine is reported to be absent or low in most publications.rises and suppressed normal thyroid tissue resumes upta#e of radioactive iodine. late development of hypothyroidism may also be a conse:uence of the damaging effects of humoral thyroid$autoantibodies triggered by * I treatment.24 of patients with an euthyroid hot nodule given * I. -owever. ((2" report no hypothyroidism in +. treated patients. /oss et al. The . <ast but not least. or the total dose of * $I administered.. 5ne possible cause of hypothyroidism is found when patients are rendered euthyroid by treatment with antithyroid drugs before radioactive iodine. In one report ((3" (* patients were followed + $ !. *$!. when the observation period after treatment is longer. . (! patients with hot nodules showed an incidence of hypothyroidism of +. below".. ((!" report no hypothyroidism in +3 patients at ! months after therapy. From these results it seems that longer follow$up periods may uncover hypothyroidism and the prevalence of this may be related to the presence of thyroid auto$ antibodies and not so much to the si9e of the thyroid nodule and the * I dose administered.14 versus . In .ome authors administer T+ for two wee#s . )o relationship was found between the development of hypothyroidism. In this situation the T.34. /atcliffe et al. the prevalence after 1 years was 3. -owever after a follow$up of 1 years reported even a percentage of hypothyroidism of +14.%dministration of * $I is also a successful mode of treatment for patients with toxic adenoma (Fig.+4 in antibody negative patients. =ight patients (*!4" had become hypothyroid. the si9e of the nodule.4 of patients with a toxic adenoma. -ypothyroidism occurred in B.

clinical observation is sufficient. This form of treatment does not increase operative ris# or histologic assessment when subse:uently necessary (* b". /esults after a follow$up of . years (* " after treatment. Figure :. but experience is very limited (* b(. Cure is virtually 114 in pre$ toxic adenomas. %fter treatment." (* a. =uthyroidism is achieved in around 3. The results are good. as stated. . (diameter * to + cm or J +1 ml resp.. * $I doses of this order give thousands of rads to the normal tissue surrounding the nodule 6oth procedures are safe.-/$antibodies in genetically susceptible sub0ects.4 of patients when assessed ( months (*1" or (. due to the production of T. serum T.4 of patients develop &raves' hyperthyroidism after treatment with * $I as has been described as well in patients similarly treated for toxic$ or euthyroid multinodular goiter. %bout . Ihatever treatment is chosen in the case of a toxic nodule.measurements at yearly intervals are . The treatment is generally well tolerated with few side effects. is percutaneous ethanol in0ection into the nodule under sonographic guidance. % more recent development in the treatment of %FT).* a " are also good especially when causing only subclinical hyperthyroidism. most patients become and remain euthyroid after treatment. /esults of ethanol in0ection in relatively large %FT). Th roid 4ith to'i# nodule before *A+ and after *?+ treat%ent 4ith 161I. <ong term treatment with antithyroid drugs is not indicated.o far this treatment seems to be effective and well tolerated. ethanol in0ection. Prognosis The prognosis for the autonomous hot nodule is that most patients remain euthyroid and. <aser photo$coagulation of %FT) is the most recently introduced therapy. Dsually in0ections are repeated ($ ( times at wee#ly intervals.usual mean doses of * $I administered for toxic nodules vary between (B! and 122 >6:.*". This author has a preference for * $I treatment in general..! months remain favorable (* b ". used as an alternative to surgery or * $I treatment. surgery or radioactive iodine or laser.

necessary to detect those patients. painless subacute thyroiditis (*!". The fre:uency then increased so that silent hyperthyroidism was responsible for about (14 of all cases of thyrotoxicosis in this geographical area in the B31's. especially with circulating thyroid autoantibodies. but the enlargement of a nodule after * $I would raise this possibility.E . . other names have been given to this syndromeE -yperthyroiditis (*(". (*+$+1" There is an association with other autoimmune diseases .chneeberg (+(" reported data obtained from a random poll indicating silent thyroiditis was uncommon in %rgentina. % retrospective survey conducted in Iisconsin (*+" from B!* through B22 showed that silent thyroiditis was not found until B!B and was uncommon up to B2*. %ffected patients are mostly between *1's and !1's and the female to male ratio is about . but in )ew For# of only (. painless thyroiditis with transient hyperthyroidism (*. there is now overwhelming evidence that it should be categori9ed as a lymphocytic thyroiditis. that will eventually develop hypothyroidism. spontaneously resolving lymphocytic thyroiditis (**". the condition is currently rarely recogni9ed. In the B31's in a study from 7apan +1 an incidence of 14 was found.. Incidence The incidence of 8painless thyroiditis8 varies with time and with geography. Etiolog %lthough the disease was earlier argued to be a mild form of subacute (?e Kuervain's" thyroiditis. The occurrence of malignancy in an autonomous or toxic nodule is very rare. atypical thyroiditis (*3" and transient thyrotoxicosis with lymphocytic thyroiditis (*B". %part from pregnancy. TOXIC M7)TINOD7)A= . 0I)ENT O= PAIN)E00 TH>=OIDITI0 !rodu#ing th roto'i#osis %lthough the terms silent thyroiditis and painless thyroiditis are most commonly used.". but occurred more fre:uently around the &reat <a#es and in Canada. DE B7E=(AIN-0 *AC7TE O= 07?AC7TE+ TH>=OIDITI0 This illness commonly referred to as subacute thyroiditis leads to temporary thyrotoxicosis in approximately half of the patients due to discharge of stored hormone from the thyroid gland.+4 (+ ". This disease is discussed in Chapter B. transient painless thyroiditis (*+". occult subacute thyroiditis (*2".tates.OITE= -yperthyroidism may occur in the multinodular thyroid gland and this is discussed in Chapter 2. =urope and the =ast$ and the Iest coast of the Dnited .

Clini#al !resentation % review (*. so characteristic of subacute thyroiditis. sometimes with the formation of lymphoid follicles. %t times persistent mild lymphocytic thyroiditis is seen. months". (++" -ere an association is found with -<% types ?/* and ?/. Forty three percent of patients had thyroid enlargement.?" months (range $ (. There is a significant association with -<% genotype ?/*. after painless thyroiditis has been documented and T.. . although symptoms such as lid lag due to increased sympathetic tone were present.ymptoms began (. thyrotoxicosis $ euthyroidism $ hypothyroidism.-/$antibodies have been found in these patients. In none of the (( episodes of silent thyroiditis was thyroidal pain present.. C/$ (. yr. These symptoms are similar to those found from other causes of thyrotoxicosis and were mild to severe. %fter a brief period of euthyroidism. This period is shorter than is usually seen with &raves' disease and certainly in multinodular toxic goiter. Patholog 5n histological examination follicles are disrupted and infiltrated predominantly by lymphocytes and by plasma cells. and euthyroidism. (+. =xophthalmos and pretibial myxedema were absent. . The follicular cells have a variable appearance. (*!a" Table 9.ostpartum thyroiditis (see below" is considered to be identical to silent thyroiditis from the phenomenological point of view. Thyroid tissue obtained during the hypothyroid or early recovery phase may show regenerating follicles with little colloid.supporting the concept that this form of thyroiditis is an autoimmune disease (+*" )o significant association has been found with viral infection. The presenting symptoms in .+ C/$ 3. )odularity of the thyroid was uncommon. =xtensive fibrosis may be present.( months preceding the initial evaluation.( yr old.ome of the hypertrophied follicular cells have an oxyphilic cytoplasm and are therefore termed -urthle or %s#ana9y cells.-.". /ecurrences were uncommon. are observed. *$2.1 (. . In *( patients clinical hypothyroidism was present.ixty$eight were female. below". 5ccasionally multinucleated giant cells. The infiltration is diffuse and/or focal.? was *(. In one patient the consistency of the thyroid was reported to be soft. but the tissue may also return to normal in others. Presenting 0 %!to%s in . their mean age C/$ . ?evelopment of &raves' disease.. while the males were (+. transient biochemical hypothyroidism developed in 2 patients. The histologic picture of postpartum thyroiditis is identical. They can be cuboidal or columnar when stimulated by T. >ean duration was *. The duration of the thyrotoxic phase was variable but for the most part lasted less than one year. . but most authors described the gland as firm. This was temporary in (+ patients but 3 re:uired thyroid hormone substitution (*!".B C/$ 3. which was generally symmetrical and enlargement was in most instances mild.( episodes of thyrotoxicosis are summari9ed in Table *$+.! C/$ (. Fifty$seven out of ( patients became euthyroid and did not develop clinical hypothyroidism.5 E!isodes of H !erth roidis% . The clinical course of the disease often follows + se:uential stages (Fig." compiled the reported clinical manifestations between B2 and B31 of ( patients with (( episodes of silent thyroiditis.

! * .. 0#he%ati# re!resentation of the four !hases of silent th roiditis *ta"en fro% ref. >yalgias/arthralgias Figure . . + * * ( ( ( ( (* 2 . Ieight loss *.0 %!to% Nu%ber of Patients Fro% Colff26. Tremor *.alpitations +. -eadache B.. -yperdefecation 2. 6. )ervousness (. B . Fatigue / malaise !. 4ith !er%ission+ . %ngina (.yncope !. Insomnia 1. . &oiter/nec# mass .2 4ith !er%ission+. Increased appetite . -eat intolerance . Irritability 3. Iea#ness +..

The hypothyroid phase may last several months. and by the latter + out of 2 were positive (*. Indicators of inflammation were not useful.* episodes./ in patients with subacute granulomatous thyroiditis and helps to differentiate the two conditions. little or no thyroglobulin is present whereas serum Tg levels are elevated in silent thyroiditis. Dpta#e may temporarily rebound above normal before returning to normal values. %ntimicrosomal antibodies were examined in . heralded by an increase in thyroid hormone levels and resumption of thyroidal radioactive iodine upta#e. discharge of hormone from the inflamed thyroid results in increases in serum T+. This contrasts to the typical mar#ed elevation of =."..". estimation of serum thyroglobulin levels is useful. %fter the third phase. The recently developed /I% for human antithyroglobulin antibodies has greater sensitivity. In 2 out of 2 patients with silent thyroiditis./". *$2. *$2". ?uring ingestion of T+. %t that time there is no upta#e of radioactive iodine in the thyroid (Fig.-. but it was greater than +1 mm/hr in only 3 (*.* patients using the complement fixation test or by microsomal fluorescence. if elevated. all were positive using this /I% (+!". *+ had elevated erythrocyte sedimentation rate (=.starts to elevate at the end of the hypothyroid phase. T* and a decrease in serum T.". The white blood cell count is generally normal. In (! . moderate elevations of antithyroglobulin antibodies were also present by tanned red cell hemagglutination assay (*.)aborator findings ?uring the first phase of the disease. Dsing the former techni:ue (( patients had positive antibodies. The erythrocyte sedimentation rate. above". T+ and T* decline into the euthyroid range (second phase" and reach subnormal levels in the hypothyroid range (third phase" in +14 of patients (Fig. . ?uring the acute phase urinary iodine excretion is high normal to elevated and after resolution of the thyroiditis reduced to /* of its original value (**" %s the first phase progresses. In . patients gradually enter the euthyroid phase.erum T. decreases gradually while thyroglobulin levels decrease as well. In a small series of 2 patients with silent thyroiditis. Ihen the diagnosis of thyrotoxicosis factitia is suspected.

+ patients. In the case of relapsing thyroiditis it is rarely necessary to perform a subtotal thyroidectomy (+1". after the onset of the hyperthyroid symptoms. but 8cured8 patients may ultimately become permanently hypothyroid (see following section". POSTPARTUM THYROIDITIS As mentioned postpartum thyroiditis is considered to be very similar if not identical to silent (painless) thyroiditis(35)." (+2a". Treat%ent %s thyrotoxicosis in silent thyroiditis is usually mild. If needed. wee#s (+2"..within the normal range. . %fter the thyrotoxic phase many patients become temporarily hypothyroid (see clinical course".1.. L adrenergic bloc#ing agents can be administered.ermanent hypothyroidism occurs in about 24 of patients with silent thyroiditis.. 5nly a small proportion of patients remain permanently hypothyroid and then full substitution with <$thyroxine is necessary. Therefore patients with painless thyroiditis should be followed thereafter at yearly intervals with appropriate testing. . In a series of . This condition is discussed in Chapter #. If it is. This phenomenon is also usually seen after withdrawal of thyroid hormone in patients treated with supraphysiological doses. treatment to relieve toxic symptoms is often not necessary.atients apparently fully recovered from silent thyroiditis may ultimately develop thyroid failure. #eeping serum T.(i. the dose should not completely compensate for the hypothyroidism since a slight T. at the end of the hypothyroid phase" is due to T. In this case prednisone can be administered in dosages ranging between +1 and !1 mg per day. This condition is discussed in Chapter 14.e. This is in contrast to subacute thyroiditis. % wea# positive correlation was reported between the echo level at the onset of thyrotoxicosis and the lowest T* level during the clinical course (p less than 1.suppression during the thyrotoxic phase. 5ften no thyroid substitution is necessary during this period. and can remain elevated for many months.. (+B" reported that in about half of patients permanent hypothyroidism ensued. Thyrotrophin levels may increase during the recovery phase. The delay time ranges between ( and . It is not useful to give antithyroid drugs because thyrotoxicosis is not the result of increased thyroid hormone synthesis. HASHIMOTO'S THYROIDITIS Occasionally ashimoto!s thyroiditis is accompanied by mild symptoms of thyroto"icosis especially in the early phases of the disease.episodes. but of discharge of thyroid hormone from the thyroid gland due to the inflammatory process. The effect of propylthyouracil or iopanoic acid to bloc# peripheral T+ to T* conversion may be of some clinical benefit. which is followed in almost all patients by permanent recovery. If more serious thyrotoxicosis is present. patients became euthyroid after a mean period of !( months. )i#olai et al. to 1 mg per wee#. usually resulting in rapid decrease of the inflammation (+3". The delayed increase of T.elevation will facilitate thyroid recovery. . %s an alternative. administration of anti$inflammatory drugs may be of benefit. %fter to ( wee#s the dose can be tapered by 2. 8thyroidectomy8 may be induced by administration of radioactive iodine during a remission.

1 )egative )egative )egative J 1. are all suppressed. (.! J .1 !B. Color flo% +oppler sono$raphy sho%s absent thyroidal vascularity and lo%. +eliberate inta)e of hi$h doses of thyroid hormone leads to T.! J ./ or TcO4. T6 Hour so%al Passi$e Anti8T.1 !1. (atients are clinically thyroto"ic& ho%ever they do not sho% eyesi$ns as seen in *raves! disease& e"cept for those related to sympathetic overactivity (lid retraction). o%ever& in patients %ith silent thyroiditis a palpable firm painless thyroid $land is present.(.(. .5). /n subacute (+e 2uervain!s) thyroiditis symptoms are typical in that& apart from thyroto"icosis& patients may have fever in the initial phase of the disease and the thyroid is very tender. 4ariotti et al. and the upta)e of 1-3. /n thyroto"icosis factitia e"cessive inta)e of thyroid hormone leads to suppression of T. (. and therefore also to suppression of thyro$lobulin lea)a$e from the thyroid $land. 3urthermore patients %ith silent thyroiditis sho% hi$h levels of thyro$lobulin.1 )egative )egative )egative .THYROTOXICOSIS FACTITIA Althou$h factitious thyroto"icosis involves all situations in %hich usa$e of (e"cessive doses) thyroid hormone leads to symptoms of thyroto"icosis& the term 'factitious' is usually associated %ith surreptitious in$estion of thyroid hormone in supraphysiolo$ical doses. /n both situations the upta)e of radioactive iodine is suppressed and patients lac) eyesi$ns. (atients usually deny ta)in$ thyroid hormones in e"cess. /n all 6 %omen thyro$lobulin %as undetectable in the serum (lo%er detection limit 1. (41a) Thus& factitious thyroto"icosis is not difficult to differentiate from thyroto"ic *raves! disease& to"ic adenoma or to"ic multinodular $oiter. Table 5. (55) performed thyro$lobulin measurements in 6 %omen %ith thyroto"icosis factitia.normal pea) systolic velocity& %hile %ith this techni0ue these si$ns are increased in *raves! disease.B J 1. 3.-5 n$7ml) (Table 13. . Th ro8 T6 =esin T0H =adio8 Antibod He%a8 =adio8 globulin 7!ta"e iodine Passi$e gglu8 assa 7!ta"e He%agglu8 tination tination E % ngD%l 7D%l E % ngDdl gDdl ND F not done *Fro% Mariotti2. This primarily psychiatric disorder may lead to %ron$ dia$nosis and treatment if physicians are not a%are of the phenomenon. They used a very sensitive thyro$lobulin assay and e"cluded the presence of thyro$lobulin antibodies that can interfere %ith the assay./ 4ith !er%ission+ J J +.1 ( J + 1 3. suppression and shrin)a$e of the thyroid& so that no thyroid tissue is palpated. Results of Thyro !"Fu#$t o# Tests # Pat e#ts % th Thyroto& $os s Fa$t t a ' Patient T9 Nu%ber Th roid 598 Mi#ro8 Anti8T.ilent thyroiditis ho%ever& is not so easily distin$uished from thyroto"icosis factitia.erum T.

1 +.(. /n more severe cases treatment %ith propranolol may be helpful..!$ J . Treatment of thyroto"icosis factitia is not difficult %ith re$ard to thyroto"ic symptoms& as discontinuation of thyroid hormone in$estion is usually sufficient.B (. T%o epidemics of . (atients may be very persistent in denyin$ the deliberate inta)e of thyroid hormone and persist in this attitude even after factitious thyroto"icosis has been une0uivocally confirmed. J 1.uppressed radioactive upta)e of the thyroid $land in combination %ith thyroto"icosis may also e"ist in patients %ith hyperfunctionin$ metastases of follicular thyroid carcinoma. J 1. .1 )egative )egative )egative )egative )egative )egative % ngDdl gDdl * + .! J .1 (.1 3. Thyroto"icosis induced by e"cessive thyroid hormone inta)e& not based on deliberate choice of the patient& has been observed in the 'hambur$er thyroto"icosis' patients. Consultation %ith a psychiatrist is ur$ently needed in such patients. T6 Hour so%al Passi$e Anti8T.2 )? !*.! J .! % ngD%l 7D%l J 1.* 3. Th ro8 T6 =esin T0H =adio8 Antibod He%a8 =adio8 globulin 7!ta"e iodine Passi$e gglu8 assa 7!ta"e He%agglu8 tination tination E .1 2+.$*1 (3$++ !. o%ever& treatment of the psychiatric disorder is more challen$in$ and may fail in the lon$ run.( ((1 J1. ! )ormal J 1.!$ 11$ *2$.1 2(.1 J J +.(.(. o%ever& in these e"tremely rare patients& thyro$lobulin levels are almost invariably elevated and radioactive iodine upta)e %ill be detected in metastases by usin$ %hole body scannin$.(.! J . .1 The possibility of this syndrome should be considered especially %hen thyroto"icosis appears to be resistant to treatment or %here laboratory data are contradictory.! J .Patient T9 Nu%ber Th roid 598 Mi#ro8 Anti8T.thyro"ine and desiccated thyroid& %hereas only T3 is elevated and T4 is lo% or non. E *.(. /t should be noted that the profile of serum thyroid hormones in thyroto"icosis factitia is determined by the composition of the preparation in$ested.3 . (!( J J +.1 1.3 )egative )egative E 11 )egative )egative )egative )egative E 11 )egative +. 8oth T4 and T3 are elevated in overdose of 9.*.detectable %hen preparations containin$ only T3 are bein$ ta)en.

li)e activity e"erted by the serum of these patients in a mouse thyroid bioassay. There is structural homolo$y %ith the >. values. 315&555 /:7l) increased serum hC* levels due to trophoblastic neoplasia %ere euthyroid. activity& it %as found that the mouse thyroid %as much more sensitive to stimulation by hC*& %hereas the human thyroid %as relatively insensitive (61).patients %ere @ud$ed to be overtly thyroto"ic& and this %as confirmed by elevated serum T4 levels. +epartment of A$riculture re$ulations.e. A variant of hC*& lac)in$ the C. /t is discussed further in the relevant chapters. 9on$. (atients %ith moderately (115&555 .= mutation increasin$ its responsiveness to hC* (5<a).tates %ere caused by inclusion of bovine thyroid in hambur$er (51&5-). increased serum free T4 and subnormal T. *estational transient thyroto"icosis (i.subunit in pituitary $lycoprotein hormones such as 9 & 3. /nclusion of the thyroid in nec) muscle trimmin$s is no% prohibited by :.terminus of the >.5 /: hC* %as found rou$hly e0uivalent to 5. Thyroto"icosis may be induced by hC* stimulation durin$ molar pre$nancy and also by trophoblastic tumors in males and in females. bioactivity in the mouse bioassay& althou$h 4555 times less than that of human T. o%ever& the >. & and a >. /n another study (51) hC* %as purified from molar tissue and had intrinsic T. .5 /: h9 %as found e0uivalent to 44 m /: hT. Thyroto"icosis and other thyroid diseases durin$ or after pre$nancy are discussed in Chapter 14.4 . /n studies usin$ thyroids from different species to test for hC* intrinsic T. for medical reasons can be desi$nated as iatro$enic (usually subclinical) thyroto"icosis. and activity of human chorionic $onadotrophin (hC*)& many healthy euthyroid pre$nant %omen have reduced serum T.145 from the >. /n a study of -5 patients (65) %ith $estational trophoblastic neoplasia . 1. This lo%er potency of hC* is caused by the C.terminal e"tension of the >. This e"tension is lac)in$ in the >.e a$t / ty of hC) ?ea) thyrotropic activity of hC* %as found in hC* prepared from pre$nancy urine& usin$ a mouse thyrotropin bioassay (5#). (63) Carbo"y peptidase di$estion of hC*& cleavin$ aminoacid residues 14-.subunit of T. suppression is usually $iven in patients after thyroidectomy for thyroid carcinoma and also to suppress beni$n thyroid $ro%th in $oiter patients.hC* unit is lar$er in that it is composed of 14< aminoacids %hile that of T. h9 also has intrinsic thyroid stimulatin$ activity& but lo%er than hC*. . uman hC* not only stimulated the mouse thyroid but . of pre$nant %omen& mostly %hen hC* levels are above <5. /n one recently reported case& thyroto"icosis %as related to a T. T. +espite this %ea) activity in hydatidiform mole disease& hC* is produced in sufficient amounts to induce hyperthyroidism. .subunit due to enAymatic cleava$e has been identified in pre$nancy serum and molar tissue (65).thyroto"icosis in the :nited . on a molar basis.patients had e"tremely hi$h serum (3&--5&555 /:7l and 6&<-5&555 /:7l) and urine hC* levels %hich correlated closely %ith T. (rescription of supranormal amounts of thyroid hormone to suppress serum T.56) THYROTOXICOSIS DU( TO PR()*A*CY A*D TROPHO+. consists of 115 aminoacids& and has additional carbohydrate residues on the COO terminus. /n another study on the activity of hC* on the human thyroid $land (6-)& 1.subunit that interferes %ith its bindin$ to the receptor. . ) is seen in 1.-< m /: hT.subunit of h9 & its structure bein$ other%ise almost identical to that of hC*. TSH l .term use of suppressive amounts of thyroid hormone has been reported to enhance osteoporosis and also cause cardiac abnormalities includin$ arrhythmias and function disturbances (53&54)& but other studies have not confirmed these findin$s (55. .subunit& leads to a dramatic increase in its capacity to stimulate adenylate cyclase in human thyroid membranes (64). hC* is composed of an alpha . .subunit& identical to the alpha . subunit %hich is specific for hC*. These .#5&555 /:7l (5<).ASTIC DIS(AS( Pre-#a#$y +ue to the intrinsic T.

= cells that decreased promptly after evacuation of the tumor (<1a). The effe$t of 2 .e# fro3 ref.# (belo%) (<<).5 cells and also causes a dose related increment of adenylate cyclase activity and thymidine upta)e (<5&<1).of so! u3 o! !e 4*AI5 a#! sur. 997 % th 0er3 ss o#5. A similar correlation bet%een serum hC* levels and thyroid stimulatin$ activity in both serum and urine %as found in t%o %omen %ho had %idely metastatic choriocarcinoma and mar)ed hyperthyroidism (65). Tro0hoblast $ ! sease Cl # $al features of tro0hoblast $ ! sease /n 1155 TisnB and co.5 o# the $ r$ulat #. hC* e"tracted from hydatidiform moles contained less sialic acid and %as biolo$ically more active than normal pre$nancy hC*(<#). hC*& possessed both $onadotrophic and thyrotropic activity. /n another patient %ith $estational choriocarcinoma serum thyroid stimulatin$ activity correlated precisely %ith serum T4& %ith the >. 8oth T. .<6) also described molar pre$nancy in combination %ith hyperthyroidism and in all cases a rapid return to normal thyroid function occurred after removal of the mole. induced adenylate cyclase stimulation %ere found more effectively inhibited by desialylated variants of hC* than unmodified hC* (61) 3rom these and other studies it seems that the biolo$ical effect of hC* is predominantly confined to hC* containin$ little or no sialic acid. subunit of human hC*& and %ith the 0uantitation of the host tumor burden (<1). receptor (6#)& desialylated forms of human hC* e"hibited stron$er inhibition of T.%or)ers described a patient %ith molar pre$nancy that had increased thyroidal upta)e of radioactive iodine and clinical si$ns of hyperthyroidism (cited by ershman and i$$ins(<-). from the plasma membrane receptor of follicular cells (61&6-&66). & and hC*. and serum T3 values in patients %ith molar pre$nancy. The youn$est patient described so far %as 1<years of a$e (<-a) A thyroid stimulator %as e"tracted from the serum of one patient that differed biolo$ically and immunolo$ically from T. /n 3i$ure 13. Carlier reports (<3. .1 (belo%) the relationship is sho%n bet%een bioassayable T. /n a later study (<-)& . The patient %as pre.era from five patients %ith hydatidiform mole before treatment sho%ed increased stimulatin$ activity in C O.R. F -ure 1. & from hC* found in normal placentas and from thyroid stimulatin$ immuno$lobulins. /n studies usin$ human thyroid membranes 6< or a cell line transfected %ith the human T. hC* has also been found to increase iodide upta)e in cultured 3=T9. mediated cA4( responses than native hC*.also displaced human T.patients %ith hydatidiform mole %ere described %ith severe hyperthyroidism and rapid disappearance of hyperthyroidism after removal of the mole.$al re3o/al of the 3olar t ssue 4O. bindin$& and T.le/els of seru3 T67 T87 hC) 4 33u#oassay5 a#! TSH 4b oassay5 # a 0at e#t % th hy!at ! for3 3ole #!u$e! thyroto& $os s 4ta.treated %ith iodide.hT. The conclusion that the molar thyrotropin differed from normal placenta hC* %as based on differences in anti$enic properties and molecular siAe. The effect of removal of molar tissue on serum T4& serum T3& bioassayable T.e. & and hC* (by immunoassay) is sho%n in 3i$ure 13. 3rom the parallelism of thyroid stimulatin$ and hC* activity it %as concluded that the same molecule& i. /n this study %ith the e"ception of one patient& there is a very hi$h correlation bet%een the t%o parameters& su$$estin$ a causal relationship bet%een serum thyrotropin activity and thyroid function. After removal of the tumor there %as a rapid normaliAation of serum T4& T3& serum T.

e# fro3 ref.. 997 % th 0er3 ss o#5. Relat o#sh 0 bet%ee# T8 seru3 le/els a#! b oassayable seru3 TSH a$t / ty # : 0at e#ts % th hy!at ! for3 3ole #!u$e! thyroto&o$os s. The $orrelat o# $oeff $ e#t for 1 0at e#ts 4e&$e0t &5 s .:6 4ta. .F -ure :.

/n patients %ho are not suitable for sur$ery because of metastatic disease& antithyroid dru$ treatment usin$ propylthyiouracil or methimaAole in combination %ith chemotherapy is the best treatment available.T. (#5) cite four cases from the literature and reported a patient %ho had choriocarcinoma of the colon associated %ith $ynecomastia and hyperthyroidism. The clinical picture of patients %ith trophoblastic hyperthyroidism is that of thyroto"icosis& lac)in$ the characteristic features belon$in$ to *raves! disease (ophthalmic disease& pretibial my"edema and acropachy). .levels are mostly above 355&555 :7l.erum thyroid stimulatin$ activity %as partly inactivated by antibovine. antiserum& but %as completely neutraliAed by anti. Or$iaAAi et al. (3or revie% see also #5a) Thera0y Obviously& removal of the tumor& if feasible& should be carried out as soon as possible./ therapy is also possible. 131. hC*. Treatment %ith antithyroid dru$s does not produce euthyroidism rapidly& and patients are therefore also treated preoperatively %ith oral sodium ipodate 1 $7day& or saturated potassium iodide 3 " 15 drops daily or sodium iodide 5. /f hyperthyroidism is so severe that development of . (ropranolol may be added to the re$imen and additional supportive therapy& replacin$ fluids and electrolytes& may be necessary. every # hours.hC* antiserum.5 $ i. Thyroid stimulatin$ activity& measured by mouse bioassay& %as detected in the serum. The thyroto"icosis is usually not severe because of its shorter duration.The clinical syndrome of hyperthyroidism associated %ith choriocarcinoma in the male is e"tremely rare& but several reports have appeared in the literature.v.

8etter results %ith macroadenomas %ere reported by . This usually consists of sur$ery plus e"ternal radiation.mallrid$e and .point of the pituitary& i. . HYP(RTHYROIDISM DU( TO A TSH S(CR(TI*) PITUITARY AD(*OMA yperthyroidism due to a T. secretin$ pituitary tumor or selective partial pituitary resistance to thyroid hormone.treatment. & in combination %ith clinical hyperthyroidism& and increased serum thyroid hormone levels& may be seen in the presence of a T. Another report (15#) described a relapse in all 4 similarly treated patients. /n 11<# Tolis et al. This approach ho%ever is not al%ays successful (15<). adenoma produce normal forms of T. is less than 1& %hereas in a T.years1(56) . The other body tissues appear more sensitive to thyroid hormones& and the clinical picture of thyroto"icosis develops.thyroid dru$ treatment should be combined %ith iodide and propranolol pre. FisualiAation of the pituitary by ma$netic resonance ima$in$ sho%s a pituitary tumor. Althou$h in principle this thyroto"icosis is not accompanied by eyesi$ns& unilateral e"ophthalmos may ensue from a thyrotropin secretin$ pituitary tumor due to invasion of one orbit (15<). but secrete them in variable amount and differin$ biolo$ical activity& e"plainin$ the variable de$ree of hyperthyroidism in these patients (154b) /n a study of 1 patients it %as found that the mean delay to a correct dia$nosis %as 6. ?hen the tumor is a macroadenoma& its behavior tends to be a$$ressive. Cye symptoms and other characteristics specific for *raves! disease are absent. DormaliAation of the elevated biolo$ic to immunolo$ic ratio of serum T.thyroid crisis after sur$ery is possible& anti. producin$ pituitary tumor (154) The criteria that are re0uired to confirm this entity are the follo%in$. producin$ pituitary tumor (see belo%) this ratio is usually above 1. alpha. . Ci$ht out of 1 %ere cured by sur$ery plus e"ternal radiation& %hereas # of 16 %ere cured by sur$ery alone and 1 out of 4 by radiation alone.e. alpha 7T. .subunits to total T. the specific T.. (153) revie%ed the literature and found that bet%een 15 . (154a). . S(. E thyroid hormone ratio needed to ensure normal thyroid $land activation& is set at a hi$her level of serum thyroid hormone concentration. (ituitary T.5 . A relapse %as seen in 4 of 5 operated and postoperatively irradiated patients durin$ follo%. /n 11#3 another revie% found 1< %omen and 16 men %ith hyperthyroidism due to a T. ?hen the dia$nosis is established& patients should have treatment of the pituitary tumor.producin$ macroadenomas. The concentration of T. This syndrome may be inherited in an autosomal dominant mode.mith (154).ince there is no pituitary tumor& the ratio of T. secretin$ pituitary tumor is rare. -5 patients had been reported. 6 years. alpha .(CTI<( TISSU( R(SISTA*C( OF TH( PITUITARY TO THYROID HORMO*( This syndrome is described in Chapter 16 and is probably part of the continuous spectrum of the syndromes of thyroid hormone resistance in %hich the resistance is predominant at the pituitary level.subunits in blood is above normal& as is the ratio of T. HYP(RTHYROIDISM DU( TO I*APPROPRIAT( TSH S(CR(TIO* Dormal or even elevated serum T. As these tumors may become invasive early treatment is advised.even of these patients %ere %ron$ly treated for presumed primary hyperthyroidism %ith either thionamides& radioactive iodine or even by thyroidectomy& prior to the final dia$nosis. after operation points to successful treatment of the adenoma (156).ince the pituitary is selectively resistant to thyroid hormone& the set.up of 3. concentration is normal or increased. 3rom these results a combination therapy consistin$ of sur$ery and irradiation seems imperative& at least in T. All patients had lar$e adenomas. The patient is clinically thyroto"ic %hile serum levels of free T4 and7or free T3 are elevated and serum T. The pro$nosis is better in patients %ith microadenomas(156).

Tyr respectively& involvin$ the third and seventh transmembrane se$ment of the thyrotropin receptor& %ere found.membrane re$ion of the T. Other abnormalities may ho%ever be present in the complicated process of thyroid hormone synthesis in carcinomatous tissue. The a$e and se" distribution in such patients is no different from that of other patients %ith follicular carcinoma& but %ithout thyroto"icosis. The syndrome is fully discussed in Chapter 16a.secretin$ adenomas. There is $enerally poor efficiency of iodine upta)e and thyroid hormone synthesis and e"cessive hormone production is due to the lar$e mass of metastatic tissue (116). . receptor. (113a) 9on$ term treatment %ith lanreotide and caber$oline has also been successful (113b). )(STATIO*A. =ecently a $ermline mutations in the e"tra. The slo% release formulation of the somatostatin analo$ lanreotide has recently been used in treatin$ a series of 1# patients %ith pituitary thyrotropin secretin$ adenomas %hich had induced hyperthyroidism. receptor %ere found to cause con$enital hyperthyroidism (114b&114c). & and normal or lo% serum T4 (116&11<&111). cells& constitutive cA4( accumulation %as observed (114&114a). . Accordin$ to Chrenheim et al (115)& 9eiter et al. /t is caused by a mutation in the T. /n . CO*)(*ITA. 3or instance& there is evidence that e"pression of the T. /n all cases %ith t%o or three monthly in@ections& there %as control of hyperthyroidism %ith mild side effects such as abdominal cramps and diarrhea.ince this %as not found in parental +DA& it represented a neo mutation.everal other $ain of function mutations have been reco$niAed& all localiAed in e"on 15 %hich encodes for the entire trans. of patients are older than 45 years and the femaleE male ratio is 3E 1. %as the first to describe& in 1146& thyroto"icosis due to functionin$ metastases in a patient %ith adenocarcinoma of the thyroid. A third mutation ((he 631 9eu) %as described in a similar patient %ith con$enital hyperthyroidism (114a). 114b ?hen mutant receptor $ene constructs %ere transfected into CO. reported -5 similar cases& and recently 54 cases reported in the literature %ere analyAed (115a).ee chapter16a. About #5. The clinical picture of thyroto"icosis is similar to the $eneral symptoms of other causes of thyroto"icosis. The metastatic pattern of this type of adenocarcinoma is as is usually found in thyroid adenocarcinoma patients& that is predominantly in bone& lun$ and mediastinum. :pta)e of radioactive iodine in metastatic tissue may be lo% in the absence of normal thyroid tissue and is often absent %hen the thyroid $land is still present.autoimmune hyperthyroidism %as ori$inally described by +upreA et al (114).Administration of dopamine a$onists or of somatostatin analo$ues are useful to shrin) the tumor and in sur$ical failures (154a&151. There %as no si$nificant chan$e in adenoma siAe.113). HYP(RTHYROIDISM Autosomal dominantly inherited non. The lanreotide in this formulation appears to be an effective medical therapy for T. HYP(RTHYROIDISM This rare syndrome consists of hyperthyroidism induced by pre$nancy. receptor in carcinomatous thyroid tissue may be absent or lo% (11#) /n many cases clinical symptoms are caused by T3 to"icosis %ith suppressed serum T. The usual dose ran$es bet%een 3<55 . C"acerbation of . receptor renderin$ it also specific for human C*(114d).cellular portion of the T.)indred!s activatin$ $ermline mutations& Fal 551 Ala and Cys 6<. <455 480 (155. THYROTOXICOSIS DU( TO M(TASTATIC THYROID CARCI*OMA /n rare situations metastatic follicular carcinoma may cause thyroto"icosis. /t is note%orthy that similar& but somatic& mutations are found in to"ic adenoma tissue (see section 'to"ic adenoma' this chapter). Treatment of metastatic functionin$ thyroid carcinoma consists of administration of radioactive iodine.-55 mCi). . The inefficient thyroid hormone synthesis is at least partly due to relative iodine deficiency in tumor tissue and the presence of abnormal thyro$lobulin (11<). Chrenheim et al. .

bloc)in$ a$ents. are beni$n (135). Treatment of struma ovarii& either %ith euthyroidism or thyroto"icosis& should be effected by removal of the ovarian tumor. The fre0uency of to"ic adenoma in patients %ith hyperthyroidism ran$es bet%een 1. The fre0uency of to"ic nodules varies in different countries. /n thyroto"icosis due to struma ovarii& upta)e of radioactive iodine of the thyroid $land is lo% in the presence of elevated serum thyroid hormones and suppressed T.occur& and this may not be a coincidence (1-1. Althou$h one %ould suspect that in thyroto"ic cases due to struma ovarii the thyroid $land %ould be reduced in siAe& the thyroid in several reports %as enlar$ed (135&13-). Also& older patients %ith a hot nodule are more li)ely to become to"ic as compared to youn$er patients. =ecently a rare case of thyroto"icosis %as described in a <3 year old %omen caused by a to"ic adenoma of the thyroid and an hyperthyroid struma ovarii (13-b) SUMMARY Thyroto"icosis arises from several etiolo$ies other than *raves! disease. /n to"ic adenoma only a hot nodule is visible on the thyroid scan. .truma ovarii is unilaterally localiAed in about 15. The possibility of developin$ thyroto"icosis in a patient %ith a hot nodule %ith a diameter of 3 cm or lar$er is -5. (ardo. Althou$h it has been postulated that thyroid carcinoma in patients %ith *raves! disease behaves more a$$ressively (1-5)& this is uncertain (1-6). as reported from different surveys. To"ic adenomas are characteriAed by a sin$le hyperactive nodule in the thyroid leadin$ to clinical and biochemical thyroto"icosis. This ris) is substantially less in smaller nodules. .1-1). STRUMA O<ARII .e"istin$ teratoma& it is sometimes difficult to determine if the thyroid tissue in the tumor is beni$n or mali$nant.truma ovarii is a rare tumor occurrin$ in a teratoma or dermoid in the ovary. +oppler flo% may aid in the preoperative dia$nosis of struma ovarii. As differentiation bet%een carcinoid and struma tissue is sometimes difficult& electron microscopic studies in combination %ith specific immunochemistry may be necessary. +efinitive treatment consists of sur$ical .truma ovarii seldom causes hyperthyroidism. /t is not advised to treat patients %ith thyroto"ic struma ovarii %ith radioiodide because of the possibility that the tumor is mali$nant& %hich cannot be determined on clinical $rounds& and secondly because of the un)no%n radiation effects on the other elements of the teratoma. There may be an association bet%een *raves! disease and thyroid carcinoma& possibly because of lon$standin$ thyroid stimulation by immuno$lobulins (1-4).=/3& neuron. Ovarian strumal carcinoid tumors have been found to synthesiAe different peptide hormones includin$ calcitonin& ACT & . Autonomous or to"ic adenomas are considered to ori$inate from somatic mutations in the $ene of *salpha protein or the $ene of the thyrotropin receptor. (ossibly this could represent the effect of thyroid stimulatin$ antibodies on both tissues.4indan and FaA0ueA (131) revie%ed the %orld literature on mali$nant struma ovarii until 11#3& findin$ only 1# cases.5 and 44.thyroto"icosis& even precipitatin$ thyroid storm& has been reported(1-5) 3or this reason radioactive iodine for therapy of a functionin$ metastatic thyroid carcinoma should be administered %ith caution and only after ade0uate preparation of the elderly patient %ith cardiovascular disease.e"istent thyroto"icosis& preparation for sur$ery should be done by administration of antithyroid dru$s& sometimes in combination %ith beta. :pta)e of radioactive iodine over the ovarian tumor confirms the dia$nosis (131a&b). in 6 years. /f normal thyroid tissue is still present& it is often advanta$eous to irradicate this tissue either by sur$ery or by radioactive iodine& to ensure more efficient upta)e of therapeutic doses of radioactive iodine in the metastatic tissue.specific enolase& chromo$ranin& synaptophysin& serotonin and other peptides (1-<. *raves! disease and follicular carcinoma occasionally co. 8lood flo% si$nals& detected from the center of the echoic lesion& and lo% resistance to flo% may be more common in struma ovarii (13-a). 8ecause of the co.5. /t is often admi"ed %ith a carcinoid tumor& (1-<) and has been reported to occur in association %ith multiple endocrine neoplasia type //A (1-#).1-3). . of patients and about #5. /n the case of co.

The other half of the patients do not become hypothyroid or& in a small minority& remain hypothyroid. arrhythmic dru$ amiodarone. Other causes of thyroto"icosis& such as multinodular $oiter& (sub)acute thyroiditis of +e 2uervain& postpartum thyroiditis and ashimoto!s thyroiditis& partial selective pituitary resistance to thyroid . =arely metastases of follicular carcinoma may result in thyroto"icosis %ith suppressed activity of the thyroid $land. Characteristically thyroid upta)e of radioactive iodine is lo% or absent and thyro$lobulin is not detectable in the serum. =elapses may be seen.ometimes addition of prednisone is necessary. Treatment consists of sur$ery %ith postoperative e"ternal irradiation. . Thyroto"icosis may be seen in association %ith elevated serum hC* activity in 1 . +esialylation of hC* renders it more biolo$ically active. /odine may be derived from iodine solutions& radio$raphic contrast a$ents and medications.ub@ects became thyroto"ic and sho%ed characteristic serum abnormalities due to inclusion of thyroid in $round beef. Thyroto"icosis due to painless thyroiditis %as uncommon until 11<3& but the reported incidence has increased since then.removal of the nodule& administration of 131/ or percutaneous administration of ethanol into the nodule. 4ost patients %ith struma ovarii are clinically and biochemically euthyroid. Treatment of the metastases %ith radioactive iodine %ill ameliorate thyroto"icosis. Treatment consists of removal of the tumor by sur$ery. The pro$nosis is better in patients %ith microadenoma. A notorious iodine containin$ a$ent is the anti. The li)elihood of mali$nancy in a to"ic nodule is very lo%. (ermanent follo%. . Amiodarone may also cause disruption of thyroid follicles resultin$ in thyroto"icosis due to release of stored iodothyronines. secretin$ pituitary tumor may cause hyperthyroidism. hC* has lo% intrinsic thyroid stimulatin$ activity& and hC* acts on the human thyroid cell throu$h the T. Treatment of the psychiatric disorder is difficult. Treatment of the pituitary tumor %ill lead to euthyroidism. . About half of the patients pass throu$h four classical phases consistin$ of thyroto"icosis& euthyroidism& hypothyroidism and bac) to euthyroidism. Another form of e"cessive thyroid hormone inta)e is the 'hambur$er thyroto"icosis'. (atients usually deny thyroid hormone tablets in$estion. The dia$nosis is strai$htfor%ard if it is suspected. This is an autoimmune thyroiditis due to lymphocytic infiltration of the thyroid and is identical to postpartum thyroiditis.truma ovarii& in itself a rare tumor occurrin$ in a teratoma or dermoid in the ovarium& rarely causes hyperthyroidism. /nappropriate T. of normal pre$nant %omen. 8iochemically characteristic is the fact that upta)e of radioactive iodine is absent in the thyroto"ic phase and the serum thyro$lobulin levels are hi$h. . +ue to its structure it may bloc) path%ays of thyroid hormone metabolism and action& leadin$ to hypothyroidism& but it can also cause hyperthyroidism due to its iodine content. Clinical thyroto"icosis is mild and treatment %ith beta bloc)in$ a$ents is often sufficient. Thyroto"icosis factitia (thyroto"icosis due to surreptitious in$estion of thyroid hormone) is primarily a psychiatric disorder.e"istin$ thyroid disease. 3urthermore& the thyroid is usually small or absent on palpation. receptor. .ur$ical removal of the mole renders the patient euthyroid. Administration of moderate or hi$h doses of iodine may induce thyroto"icosis in patients %ith or %ithout apparent pre. ?hen values are above 355&555 :7l& thyroto"icosis is li)ely. /n hydatidiform mole disease ho%ever& hi$h levels are found in patients! serum. Althou$h complete recovery is the rule& these patients are at hi$h ris) of developin$ hypothyroidism in later years.up is therefore necessary.. Administration of dopamine anta$onists or somatostatin analo$ues has been sho%n to be successful as %ell. secretion by a T.

=eturn to top .hormone& inherited to"ic hyperplasia and $estational hyperthyroidism are considered else%here in this volume.