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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.

The functional development of a toxic adenoma of the thyroid is from a 8warm8 nodule via a 8hot8 nodule to a 8toxic8 nodule. % warm nodule is defined as a nodule that cannot scintigraphically be distinguished from the normal surrounding thyroidal tissue, whereas a 8hot8 nodule has more activity than the surrounding tissue. % nodule that is 8hot8 on scintiscan may not actually overproduce hormone in which case serum T,- is still in the normal range and extranodular thyroid tissue is visible on the thyroid scan. The difference between a 8hot8 and a 8toxic8 nodule is that in the latter T,- is suppressed and there is typically no activity visible on the scan outside the nodule. It is unusual that an autonomously functioning thyroid nodule is toxic when the diameter is less than * cm. ( *, +"

%pproximately in 1, to in (1 solitary nodules present with hyperthyroidism. This varies from country to country, being more common in =urope than in the D,%. ( *, ;"The problem is ; times more common in women than men. In a group of *+B patients with autonomous functioning thyroid nodules (%FT)" -amburger found 34 to be toxic. The proportion of cases of %FT) with hyperthyroidism was **4 in males, but only 24 in females. * Forty$eight percent of euthyroid sub0ects were +1 years or older, whereas 2*4 of hyperthyroid patients fell in this age group. 5f the group of patients !1 years or older, ;24 were toxic, whereas this was the case only in *4 of patients younger than !1 years. Two$hundred$thirteen patients had nodules up to (.; cm in diameter and of these only .B4 were toxic. In the remaining *! patients with larger nodules, +(.!4 were toxic. 5f the (!! patients who were younger than +1 years only B.;4 had nodules * cm in diameter or larger, whereas in the older patients this figure was +;.B4. These data underline the fact that larger %FT) occur in the older age group and that at the time of presentation, nodules less than (.; cm in diameter are rarely toxic. The fre:uency of toxic adenoma in patients referred for thyrotoxicosis may vary considerably in different geographical areas. .ercentages between .; and ++.; have been reported (see Table *$ ". In =urope a female to male ratio of ;E was reported for toxic autonomous nodules ( !". Table 1. Fre&uen# of To'i# Adeno%a in (arious Countries



No. of Th roto'i# Patients

Per#ent of To'i# Adeno%as

*a+ ,ra$es- disease !lus to'i# adeno%as. *b+ Th roto'i#osis sub%itted to surger . *#+ Patients under ./ ears of age. *d+ 0i' ears after bread iodination. *Fro% Orgia11i2 *31+ 4ith !er%ission.+ Europe %ustria B!!$ B!3 3( ++.;

)o#ation =ngland Finland France .aris >arseille >ontpellier &ermany &reece Italy ,wit9erland &eneral ,urvey North America Cleveland )ew For# /ochester /ochester ,outhfield >I Australia

Period B+3 B!B

No. of Th roto'i# Patients 12 (; *.2 3

Per#ent of To'i# Adeno%as

B!( B!+ B!;$ B!2 B!; B!3 B!3 B!2 B3!

(+ ;*2 (+1 *;1 !3! , ( $$ B(+ ** (+


B.2 B.; .+


B!( B++ B ( B;+$ B!; B! $ B2B

(,3+!(a" (,+* (b" ,!(2 ( ; $$ (

.! .; (*.B ;.3

)o#ation Tasmania

Period B2* (d"

No. 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 (+.3 per 11,111" with that between B21 and B2+. )o difference in incidence was found ( !a"

Natural histor
%utonomously functioning nodules may stay the same si9e, grow, degenerate or become gradually toxic. In one series 14 of patients followed for ! years became toxic. Toxicity may develop independent of age, but is much more common in nodules over * cm in diameter (up to (14" ( *". 6y sonography the critical volume at which hyperthyroidism will occur, was ! ml( 2". Changes in nodule si9e as observed in ;B patients followed between $ ; years ( *" are shown in Table *$(. %n increase in si9e was seen in only 14. Four percent decreased in si9e. <oss of function was seen in + patients because of degeneration. =ight percent developed overt thyrotoxicosis in a mean follow$up of * to ; years. Three percent developed borderline hyperthyroidism (Table *$*".

5n macroscopic examination, a solitary toxic nodule is surrounded by normal thyroid tissue that is functionally suppressed. >icroscopically one would expect, on the basis of current ideas about pathogenesis, to see the picture of a true adenoma with uniform thyroid follicles and without characteristics of malignancy. ,tuder et al. ( ,("found that hot nodules in so$called multinodular goiter, appear occasionally to be monoclonal in function ( as has also been shown to be the case on the basis of somatic point mutations in the T,-$/ gene (see Chapt. 2", but usually are composed of heterogeneous follicles of different si9es and different capacity to ta#e up radioactive iodine (Fig. *$(". %lthough such heterogeneity has been identified in multinodular goiters, it is apparent that also in the isolated toxic adenoma multifunctional follicles appear to be present (Fig. *$*, below". This multifocal histological picture however should not a priori be interpreted as suggestive of heterogeneous origin. Thus it is :uite possible that, as in multinodular goiter (see Ch. 2", although of monoclonal origin, secondary ac:uisition of new inheritable :ualities by replicating cells, renders the function and the histological picture of the follicles heterogeneous. 5ld hemorrhage, sometimes reflected by calcification, may also be present in toxic adenomas. 5n microscopic examination of a thyroid with a clinically single toxic adenoma, autonomously functioning micronodules are seen in the extranodular tissue. This finding is in agreement with the thesis of ,tuder et al. ( ,(" 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, whereas the grossly abnormal multinodular goiter is situated at the other end of the scale. Figure 5. 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. 12 4ith !er%ission+.

Figure 6. 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. 52 4ith !er%ission+.

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

Duration of Follo487! * r+ Change in Nodule 0i1e 185 689 .8: ;81. Total

<2 Nodule in#reased in si1e2 82 nodule de#reased in si1e. *a+ One additional !atient !resented 4ith a#ute nodular enlarge%ent and T6 to'i#osis2 both of 4hi#h subsides s!ontaneousl . *Fro% Ha%burder2 *16+ 4ith !er%ission.+ C cm or more and became toxic C cm or more, euthyroid C cm or more, euthyroid, degeneration )o change )o change, degeneration )o change, toxic $ cm or more C cm, transient toxicity, then $ cm Total ((a" 2B 1 +( !1 * ; ( + * 1 *2 1 * * 1 ( 1 2 + 1 1 ! ( ;B + 1 1 1 1 1 ; 1 + B ( ((

Table 6. =esults of Follo48u! of 7ntreated Patients 4ith Nonto'i# AFTN

Duration of Follo487! * r+ Author Countr >ear No. of ?orderline =ange Mean H !erth roid Patients H !erth roid

*Fro% Ha%burger2 *16+ 4ith !er%ission.+ >cCormac# D.,. B!2 + (.;$3.; +.3 1

Duration of Follo487! * r+ Author ,ilverstein >iller 6urman 6lum Countr D.,. D.,. D.,. D.,. >ear B!2 B!3 B2+ B2; B2; ; No. of ?orderline =ange Mean H !erth roid Patients H !erth roid B ; +3 * H $ ( $ ; /($* $ .3 + ! *.* *.; ($2 $2 /*$ .* + * ( 1 1 1 + 1 + 1 ( 1 1 1 !

-amburger D.,. -amburger D.,. <obo Ieiner 6ra9il

Current ;B B!; ; ;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, the finding of a suppressed serum T,- value theoretically is sufficient to establish the diagnosis of a toxic nodule. -owever, to ascertain the severity of thyroid overactivity, measurement of a serum (free" T+ (and when normal of serum (free" T*" is important. It is wise to obtain a thyroid scan, preferably using (*$I. The scan of a toxic nodule will show prominent upta#e in the nodule with little or no upta#e in surrounding thyroid tissue, and will show appreciably less upta#e in the surrounding tissue in the case of a hot nodule. %s Tc5+$ is not organified in thyroid tissue (in contrast to radioactive iodine", discrepancies are occasionally seen. (Fig. *$+" /are nodules may be hot with Tc5+$, while being cold on scanning using radioactive iodine. In these situations the nodule should be considered cold and therefore of malignant potential. It is therefore advised that if a nodule shows prominent activity with technetium, the scan should be repeated using I (* ( B". This is not necessary however, if T,- is suppressed, indicating hyperthyroidism.

Figure 9. 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+.

The presence of carcinoma in a toxic or hot nodule is rare. -orst et al. ( !" found no thyroid malignancy in a study of *1! patients with %FT). ,ander et al. ((1" reviewed the literature on occurrence of carcinoma in a solitary hyperfunctioning nodule. They also concluded that the incidence of malignancy in a hot thyroid nodule is exceedingly low. Isolated cases of carcinoma development in a hot nodule have however been reported. (( ,((" % study from the Dnited ,tates ((*" reported the occurrence of * carcinomas in *1 consecutive patients operated for solitary hot nodules. (-owever some authors suggest that occurrence of carcinoma in %FT) may be more than coincidental. ((+" 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, the possibility of the presence of &raves' disease in remnant thyroid tissue (e.g. after previous thyroidectomy or in thyroid dysgenesis" is remote. The ultimate proof that surrounding tissue is suppressed but present can only be obtained after administration of r$T,- and subse:uent scanning of the thyroid. -owever, this is virtually never re:uired to establish the diagnosis. Dltrasound will often reveal a small contralateral thyroid lobe as well as the dominant nodule, but again adds little to the evaluation. 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, if not impossible. This can lead to a high proportion of false positive cytological diagnoses of follicular carcinoma. Ihen a hot nodule is present, but there is still (be it less" upta#e of isotope in surrounding tissue and serum T,- is within normal limits, autonomous function of the nodule can be proven by administration of T+ ((11 ug/day for + days". %fter this a repeat thyroid scan should show that the surrounding tissue is inactive because of suppression of serum T,-. -owever, this procedure has no practical conse:uences and is therefore unnecessary in clinical practice.


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

%dministration of * $I is also a successful mode of treatment for patients with toxic adenoma (Fig. *$!, below". The prevalence of hypothyroidism after treatment with radioactive iodine is reported to be absent or low in most publications. /atcliffe et al. ((!" report no hypothyroidism in +3 patients at ! months after therapy. %lso at the same time after therapy, /oss et al. ((2" report no hypothyroidism in +; treated patients. -owever, when the observation period after treatment is longer, hypothyroidism may be documented. In one report ((3" (* patients were followed + $ !.; years after treatment. =ight patients (*!4" had become hypothyroid. The incidence of hypothyroidism was not related to nodule si9e, the level of thyroid function at therapy, or the total dose of * $I administered. In ;+4 of patients nodules were still palpable. In a similar study ((B", (! patients with hot nodules showed an incidence of hypothyroidism of +.34, 1 years after * $I treatment. )o relationship was found between the development of hypothyroidism, the si9e of the nodule, or the total amount of administered radioactivity. -ypothyroidism occurred in B.24 of patients with an euthyroid hot nodule given * I, and in only .;4 of patients with a toxic adenoma. Ihen antithyroglobulin and/or antithyroid microsomal antibodies were present, the prevalence after 1 years was 3.14 versus .+4 in antibody negative patients. -owever after a follow$up of 1 years reported even a percentage of hypothyroidism of +14. 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. 5ne possible cause of hypothyroidism is found when patients are rendered euthyroid by treatment with antithyroid drugs before radioactive iodine. In this situation the T,- rises and suppressed normal thyroid tissue resumes upta#e of radioactive iodine, and therefore is damaged by the isotope. ,ome authors administer T+ for two wee#s , prior to * $I treatment to be sure that the normal surrounding thyroid tissue is suppressed. It is also possible that high doses of * I in the nodule provide enough radiation to the surrounding tissue that its function is seriously damaged. <ast but not least, late development of hypothyroidism may also be a conse:uence of the damaging effects of humoral thyroid$autoantibodies triggered by * I treatment. The

usual mean doses of * $I administered for toxic nodules vary between (B! and 122 >6:. %bout ;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, due to the production of T,-/$antibodies in genetically susceptible sub0ects. * $I doses of this order give thousands of rads to the normal tissue surrounding the nodule 6oth procedures are safe. This author has a preference for * $I treatment in general. Figure :. Th roid 4ith to'i# nodule before *A+ and after *?+ treat%ent 4ith 161I.

% more recent development in the treatment of %FT), used as an alternative to surgery or * $I treatment, is percutaneous ethanol in0ection into the nodule under sonographic guidance. The results are good. =uthyroidism is achieved in around 3;4 of patients when assessed ( months (*1" or (.; years (* " after treatment. Cure is virtually 114 in pre$ toxic adenomas. Dsually in0ections are repeated ($ ( times at wee#ly intervals. The treatment is generally well tolerated with few side effects. /esults of ethanol in0ection in relatively large %FT), (diameter * to + cm or J +1 ml resp." (* a,* a " are also good especially when causing only subclinical hyperthyroidism. This form of treatment does not increase operative ris# or histologic assessment when subse:uently necessary (* b". /esults after a follow$up of ;! months remain favorable (* b ". <aser photo$coagulation of %FT) is the most recently introduced therapy, but experience is very limited (* b(,*". ,o far this treatment seems to be effective and well tolerated.

The prognosis for the autonomous hot nodule is that most patients remain euthyroid and, as stated, clinical observation is sufficient. Ihatever treatment is chosen in the case of a toxic nodule, ethanol in0ection, surgery or radioactive iodine or laser, most patients become and remain euthyroid after treatment. <ong term treatment with antithyroid drugs is not indicated. %fter treatment, serum T,- measurements at yearly intervals are

necessary to detect those patients, especially with circulating thyroid autoantibodies, that will eventually develop hypothyroidism. The occurrence of malignancy in an autonomous or toxic nodule is very rare, but the enlargement of a nodule after * $I would raise this possibility.


-yperthyroidism may occur in the multinodular thyroid gland and this is discussed in Chapter 2.


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. This disease is discussed in Chapter B.

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, other names have been given to this syndromeE -yperthyroiditis (*(", spontaneously resolving lymphocytic thyroiditis (**", transient painless thyroiditis (*+", painless thyroiditis with transient hyperthyroidism (*;", painless subacute thyroiditis (*!", occult subacute thyroiditis (*2", atypical thyroiditis (*3" and transient thyrotoxicosis with lymphocytic thyroiditis (*B". Incidence The incidence of 8painless thyroiditis8 varies with time and with geography. % 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*. 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. In the B31's in a study from 7apan +1 an incidence of 14 was found, but in )ew For# of only (.+4 (+ ". ,chneeberg (+(" reported data obtained from a random poll indicating silent thyroiditis was uncommon in %rgentina, =urope and the =ast$ and the Iest coast of the Dnited ,tates, but occurred more fre:uently around the &reat <a#es and in Canada. %ffected patients are mostly between *1's and !1's and the female to male ratio is about .;E . %part from pregnancy, the condition is currently rarely recogni9ed.

%lthough the disease was earlier argued to be a mild form of subacute (?e Kuervain's" thyroiditis, there is now overwhelming evidence that it should be categori9ed as a lymphocytic thyroiditis. (*+$+1" There is an association with other autoimmune diseases

supporting the concept that this form of thyroiditis is an autoimmune disease (+*" )o significant association has been found with viral infection. There is a significant association with -<% genotype ?/*. .ostpartum thyroiditis (see below" is considered to be identical to silent thyroiditis from the phenomenological point of view. (++" -ere an association is found with -<% types ?/* and ?/; (+;".

5n histological examination follicles are disrupted and infiltrated predominantly by lymphocytes and by plasma cells. The infiltration is diffuse and/or focal, sometimes with the formation of lymphoid follicles. The follicular cells have a variable appearance. They can be cuboidal or columnar when stimulated by T,-. ,ome of the hypertrophied follicular cells have an oxyphilic cytoplasm and are therefore termed -urthle or %s#ana9y cells. Thyroid tissue obtained during the hypothyroid or early recovery phase may show regenerating follicles with little colloid. %t times persistent mild lymphocytic thyroiditis is seen, but the tissue may also return to normal in others. =xtensive fibrosis may be present. 5ccasionally multinucleated giant cells, so characteristic of subacute thyroiditis, are observed. The histologic picture of postpartum thyroiditis is identical.

Clini#al !resentation
% review (*;" compiled the reported clinical manifestations between B2 and B31 of ( patients with (( episodes of silent thyroiditis. ,ixty$eight were female, their mean age C/$ ,? was *(.+ C/$ 3.; yr. while the males were (+.B C/$ 3.( yr old. In none of the (( episodes of silent thyroiditis was thyroidal pain present. /ecurrences were uncommon. The presenting symptoms in ;( episodes of thyrotoxicosis are summari9ed in Table *$+. These symptoms are similar to those found from other causes of thyrotoxicosis and were mild to severe. The duration of the thyrotoxic phase was variable but for the most part lasted less than one year. >ean duration was *.! C/$ (.1 (,?" months (range $ (.; months". ,ymptoms began (.; C/$ (.( months preceding the initial evaluation. This period is shorter than is usually seen with &raves' disease and certainly in multinodular toxic goiter. =xophthalmos and pretibial myxedema were absent, although symptoms such as lid lag due to increased sympathetic tone were present. In one patient the consistency of the thyroid was reported to be soft, but most authors described the gland as firm. Forty three percent of patients had thyroid enlargement, which was generally symmetrical and enlargement was in most instances mild. )odularity of the thyroid was uncommon. The clinical course of the disease often follows + se:uential stages (Fig. *$2, below", thyrotoxicosis $ euthyroidism $ hypothyroidism, and euthyroidism. Fifty$seven out of ( patients became euthyroid and did not develop clinical hypothyroidism. %fter a brief period of euthyroidism, transient biochemical hypothyroidism developed in 2 patients. In *( patients clinical hypothyroidism was present. This was temporary in (+ patients but 3 re:uired thyroid hormone substitution (*!". ?evelopment of &raves' disease, after painless thyroiditis has been documented and T,-/$antibodies have been found in these patients. (*!a" Table 9. Presenting 0 %!to%s in .5 E!isodes of H !erth roidis%

0 %!to%

Nu%ber of Patients

Fro% Colff26. 4ith !er%ission+ . )ervousness (. Ieight loss *. .alpitations +. -eat intolerance ;. Fatigue / malaise !. -yperdefecation 2. Irritability 3. -eadache B. Insomnia 1. Increased appetite . %ngina (. Tremor *. Iea#ness +. &oiter/nec# mass ;. ,yncope !. >yalgias/arthralgias Figure ;. 0#he%ati# re!resentation of the four !hases of silent th roiditis *ta"en fro% ref. 6.2 4ith !er%ission+. B ; + * * ( ( ( ( (* 2 ;! *

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

episodes, patients became euthyroid after a mean period of !( months, after the onset of the hyperthyroid symptoms. Thyrotrophin levels may increase during the recovery phase, and can remain elevated for many months. The delayed increase of T,- (i.e. at the end of the hypothyroid phase" is due to T,- suppression during the thyrotoxic phase. This phenomenon is also usually seen after withdrawal of thyroid hormone in patients treated with supraphysiological doses. The delay time ranges between ( and ; wee#s (+2". .ermanent hypothyroidism occurs in about 24 of patients with silent thyroiditis, but 8cured8 patients may ultimately become permanently hypothyroid (see following section". % 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 1.1;" (+2a".

%s thyrotoxicosis in silent thyroiditis is usually mild, treatment to relieve toxic symptoms is often not necessary. If needed, L adrenergic bloc#ing agents can be administered. It is not useful to give antithyroid drugs because thyrotoxicosis is not the result of increased thyroid hormone synthesis, 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. If more serious thyrotoxicosis is present, administration of anti$inflammatory drugs may be of benefit. In this case prednisone can be administered in dosages ranging between +1 and !1 mg per day, usually resulting in rapid decrease of the inflammation (+3". %fter to ( wee#s the dose can be tapered by 2.; to 1 mg per wee#. In the case of relapsing thyroiditis it is rarely necessary to perform a subtotal thyroidectomy (+1". %s an alternative, 8thyroidectomy8 may be induced by administration of radioactive iodine during a remission. %fter the thyrotoxic phase many patients become temporarily hypothyroid (see clinical course". 5ften no thyroid substitution is necessary during this period. If it is, the dose should not completely compensate for the hypothyroidism since a slight T,elevation will facilitate thyroid recovery. 5nly a small proportion of patients remain permanently hypothyroid and then full substitution with <$thyroxine is necessary, #eeping serum T,- within the normal range. .atients apparently fully recovered from silent thyroiditis may ultimately develop thyroid failure. In a series of ;+ patients, )i#olai et al. (+B" reported that in about half of patients permanent hypothyroidism ensued. This is in contrast to subacute thyroiditis, which is followed in almost all patients by permanent recovery. Therefore patients with painless thyroiditis should be followed thereafter at yearly intervals with appropriate testing.
POSTPARTUM THYROIDITIS As mentioned postpartum thyroiditis is considered to be very similar if not identical to silent (painless) thyroiditis(35). This condition is discussed in Chapter 14. HASHIMOTO'S THYROIDITIS Occasionally ashimoto!s thyroiditis is accompanied by mild symptoms of thyroto"icosis especially in the early phases of the disease. This condition is discussed in Chapter #.

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. (atients usually deny ta)in$ thyroid hormones in e"cess. This primarily psychiatric disorder may lead to %ron$ dia$nosis and treatment if physicians are not a%are of the phenomenon. (atients are clinically thyroto"ic& ho%ever they do not sho% eyesi$ns as seen in *raves! disease& e"cept for those related to sympathetic overactivity (lid retraction). +eliberate inta)e of hi$h doses of thyroid hormone leads to T, suppression and shrin)a$e of the thyroid& so that no thyroid tissue is palpated. ,erum T, and the upta)e of 1-3./ or TcO4. are all suppressed. Color flo% +oppler sono$raphy sho%s absent thyroidal vascularity and lo%.normal pea) systolic velocity& %hile %ith this techni0ue these si$ns are increased in *raves! disease. (41a) Thus& factitious thyroto"icosis is not difficult to differentiate from thyroto"ic *raves! disease& to"ic adenoma or to"ic multinodular $oiter. /n subacute (+e 2uervain!s) thyroiditis symptoms are typical in that& apart from thyroto"icosis& patients may have fever in the initial phase of the disease and the thyroid is very tender. ,ilent thyroiditis ho%ever& is not so easily distin$uished from thyroto"icosis factitia. /n both situations the upta)e of radioactive iodine is suppressed and patients lac) eyesi$ns. o%ever& in patients %ith silent thyroiditis a palpable firm painless thyroid $land is present. 3urthermore patients %ith silent thyroiditis sho% hi$h levels of thyro$lobulin. /n thyroto"icosis factitia e"cessive inta)e of thyroid hormone leads to suppression of T, and therefore also to suppression of thyro$lobulin lea)a$e from the thyroid $land. 4ariotti et al. (55) performed thyro$lobulin measurements in 6 %omen %ith thyroto"icosis factitia. They used a very sensitive thyro$lobulin assay and e"cluded the presence of thyro$lobulin antibodies that can interfere %ith the assay. /n all 6 %omen thyro$lobulin %as undetectable in the serum (lo%er detection limit 1.-5 n$7ml) (Table 13.5). Table 5. Results of Thyro !"Fu#$t o# Tests # Pat e#ts % th Thyroto& $os s Fa$t t a '

Patient T9 Nu%ber

Th roid 598 Mi#ro8 Anti8T, T6 Hour so%al Passi$e Anti8T, Th ro8 T6 =esin T0H =adio8 Antibod He%a8 =adio8 globulin 7!ta"e iodine Passi$e gglu8 assa 7!ta"e He%agglu8 tination tination E % ngD%l 7D%l E

% ngDdl gDdl

ND F not done *Fro% Mariotti2./ 4ith !er%ission+ J J +;1 !B. 3.1 ( J + 1 3.1 !1.B J 1.! J .(; (.1 )egative )egative )egative

J 1.! J .(;



)egative )egative

Patient T9 Nu%ber

Th roid 598 Mi#ro8 Anti8T, T6 Hour so%al Passi$e Anti8T, Th ro8 T6 =esin T0H =adio8 Antibod He%a8 =adio8 globulin 7!ta"e iodine Passi$e gglu8 assa 7!ta"e He%agglu8 tination tination E ;*.! % ngD%l 7D%l J 1.! J .(; J 1.! J .(; E *.1 (.1 )egative )egative )egative )egative )egative )egative

% ngDdl gDdl * + .; (!(

J J +;1 2+.1 3.1 J J +;1 2(.* 3.1 +.2 )? !*.3

; ! )ormal

J 1.! J .(; J 1.! J .(;

.1 1.3

)egative )egative E 11

)egative )egative )egative )egative E 11 )egative

+.!$ 11$ *2$;B (.( ((1

J1.!$ J .(;$*1 (3$++ !.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. (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. Consultation %ith a psychiatrist is ur$ently needed in such patients. ,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. 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$. /t should be noted that the profile of serum thyroid hormones in thyroto"icosis factitia is determined by the composition of the preparation in$ested. 8oth T4 and T3 are elevated in overdose of 9.thyro"ine and desiccated thyroid& %hereas only T3 is elevated and T4 is lo% or non.detectable %hen preparations containin$ only T3 are bein$ ta)en. 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. /n more severe cases treatment %ith propranolol may be helpful. o%ever& treatment of the psychiatric disorder is more challen$in$ and may fail in the lon$ run. 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. T%o epidemics of

thyroto"icosis in the :nited ,tates %ere caused by inclusion of bovine thyroid in hambur$er (51&5-). /nclusion of the thyroid in nec) muscle trimmin$s is no% prohibited by :, +epartment of A$riculture re$ulations. (rescription of supranormal amounts of thyroid hormone to suppress serum T, for medical reasons can be desi$nated as iatro$enic (usually subclinical) thyroto"icosis. T, suppression is usually $iven in patients after thyroidectomy for thyroid carcinoma and also to suppress beni$n thyroid $ro%th in $oiter patients. /t is discussed further in the relevant chapters. 9on$.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$s (55.56) THYROTOXICOSIS DU( TO PR()*A*CY A*D TROPHO+,ASTIC DIS(AS( Pre-#a#$y +ue to the intrinsic T, .li)e activity of human chorionic $onadotrophin (hC*)& many healthy euthyroid pre$nant %omen have reduced serum T, values. *estational transient thyroto"icosis (i.e. increased serum free T4 and subnormal T, ) is seen in 1.4 ; of pre$nant %omen& mostly %hen hC* levels are above <5.#5&555 /:7l (5<). /n one recently reported case& thyroto"icosis %as related to a T, .= mutation increasin$ its responsiveness to hC* (5<a). Thyroto"icosis and other thyroid diseases durin$ or after pre$nancy are discussed in Chapter 14. Thyroto"icosis may be induced by hC* stimulation durin$ molar pre$nancy and also by trophoblastic tumors in males and in females. hC* is composed of an alpha .subunit& identical to the alpha .subunit in pituitary $lycoprotein hormones such as 9 & 3, and T, & and a >. subunit %hich is specific for hC*. There is structural homolo$y %ith the >.subunit of T, . o%ever& the >.hC* unit is lar$er in that it is composed of 14< aminoacids %hile that of T, consists of 115 aminoacids& and has additional carbohydrate residues on the COO terminus. TSH l .e a$t / ty of hC) ?ea) thyrotropic activity of hC* %as found in hC* prepared from pre$nancy urine& usin$ a mouse thyrotropin bioassay (5#). /n another study (51) hC* %as purified from molar tissue and had intrinsic T, bioactivity in the mouse bioassay& althou$h 4555 times less than that of human T, on a molar basis. +espite this %ea) activity in hydatidiform mole disease& hC* is produced in sufficient amounts to induce hyperthyroidism. /n a study of -5 patients (65) %ith $estational trophoblastic neoplasia - patients %ere @ud$ed to be overtly thyroto"ic& and this %as confirmed by elevated serum T4 levels. These - patients had e"tremely hi$h serum (3&--5&555 /:7l and 6&<-5&555 /:7l) and urine hC* levels %hich correlated closely %ith T, .li)e activity e"erted by the serum of these patients in a mouse thyroid bioassay. (atients %ith moderately (115&555 . 315&555 /:7l) increased serum hC* levels due to trophoblastic neoplasia %ere euthyroid. /n studies usin$ thyroids from different species to test for hC* intrinsic T, activity& it %as found that the mouse thyroid %as much more sensitive to stimulation by hC*& %hereas the human thyroid %as relatively insensitive (61). /n another study on the activity of hC* on the human thyroid $land (6-)& 1.5 /: hC* %as found rou$hly e0uivalent to 5.-< m /: hT, . h9 also has intrinsic thyroid stimulatin$ activity& but lo%er than hC*. 1.5 /: h9 %as found e0uivalent to 44 m /: hT, . This lo%er potency of hC* is caused by the C.terminal e"tension of the >.subunit that interferes %ith its bindin$ to the receptor. This e"tension is lac)in$ in the >.subunit of h9 & its structure bein$ other%ise almost identical to that of hC*. (63) Carbo"y peptidase di$estion of hC*& cleavin$ aminoacid residues 14-.145 from the >.subunit& leads to a dramatic increase in its capacity to stimulate adenylate cyclase in human thyroid membranes (64). A variant of hC*& lac)in$ the C.terminus of the >.subunit due to enAymatic cleava$e has been identified in pre$nancy serum and molar tissue (65). uman hC* not only stimulated the mouse thyroid but

also displaced human T, from the plasma membrane receptor of follicular cells (61&6-&66). /n studies usin$ human thyroid membranes 6< or a cell line transfected %ith the human T, receptor (6#)& desialylated forms of human hC* e"hibited stron$er inhibition of T, mediated cA4( responses than native hC*. 8oth T, bindin$& and T, 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. hC* has also been found to increase iodide upta)e in cultured 3=T9.5 cells and also causes a dose related increment of adenylate cyclase activity and thymidine upta)e (<5&<1). Tro0hoblast $ ! sease Cl # $al features of tro0hoblast $ ! sease /n 1155 TisnB and co.%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$$ins(<-). Carlier reports (<3.<6) also described molar pre$nancy in combination %ith hyperthyroidism and in all cases a rapid return to normal thyroid function occurred after removal of the mole. The effect of removal of molar tissue on serum T4& serum T3& bioassayable T, & and hC* (by immunoassay) is sho%n in 3i$ure 13.# (belo%) (<<). The patient %as pre.treated %ith iodide. After removal of the tumor there %as a rapid normaliAation of serum T4& T3& serum T, & and hC*. 3rom the parallelism of thyroid stimulatin$ and hC* activity it %as concluded that the same molecule& i.e. hC*& possessed both $onadotrophic and thyrotropic activity. /n a later study (<-)& - patients %ith hydatidiform mole %ere described %ith severe hyperthyroidism and rapid disappearance of hyperthyroidism after removal of the mole. The youn$est patient described so far %as 1<years of a$e (<-a) A thyroid stimulator %as e"tracted from the serum of one patient that differed biolo$ically and immunolo$ically from T, & from hC* found in normal placentas and from thyroid stimulatin$ immuno$lobulins. The conclusion that the molar thyrotropin differed from normal placenta hC* %as based on differences in anti$enic properties and molecular siAe. hC* e"tracted from hydatidiform moles contained less sialic acid and %as biolo$ically more active than normal pre$nancy hC*(<#). /n 3i$ure 13.1 (belo%) the relationship is sho%n bet%een bioassayable T, and serum T3 values in patients %ith molar pre$nancy. /n this study %ith the e"ception of one patient& there is a very hi$h correlation bet%een the t%o parameters& su$$estin$ a causal relationship bet%een serum thyrotropin activity and thyroid function. 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). /n another patient %ith $estational choriocarcinoma serum thyroid stimulatin$ activity correlated precisely %ith serum T4& %ith the >. subunit of human hC*& and %ith the 0uantitation of the host tumor burden (<1). ,era from five patients %ith hydatidiform mole before treatment sho%ed increased stimulatin$ activity in C O.hT, = cells that decreased promptly after evacuation of the tumor (<1a). F -ure 1. The effe$t of 2 - of so! u3 o! !e 4*AI5 a#! sur- $al re3o/al of the 3olar t ssue 4O.R.5 o# the $ r$ulat #- le/els of seru3 T67 T87 hC) 4 33u#oassay5 a#! TSH 4b oassay5 # a 0at e#t % th hy!at ! for3 3ole #!u$e! thyroto& $os s 4ta.e# fro3 ref. 997 % th 0er3 ss o#5.

F -ure :. 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.e# fro3 ref. 997 % th 0er3 ss o#5.

The clinical syndrome of hyperthyroidism associated %ith choriocarcinoma in the male is e"tremely rare& but several reports have appeared in the literature. Or$iaAAi et al. (#5) cite four cases from the literature and reported a patient %ho had choriocarcinoma of the colon associated %ith $ynecomastia and hyperthyroidism. Thyroid stimulatin$ activity& measured by mouse bioassay& %as detected in the serum. ,erum thyroid stimulatin$ activity %as partly inactivated by antibovine.T, antiserum& but %as completely neutraliAed by anti.hC* antiserum. 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). hC*.levels are mostly above 355&555 :7l. The thyroto"icosis is usually not severe because of its shorter duration. (3or revie% see also #5a) Thera0y Obviously& removal of the tumor& if feasible& should be carried out as soon as possible. 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 5.5 $ i.v. every # hours. (ropranolol may be added to the re$imen and additional supportive therapy& replacin$ fluids and electrolytes& may be necessary. /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. 131./ therapy is also possible. /f hyperthyroidism is so severe that development of

thyroid crisis after sur$ery is possible& anti.thyroid dru$ treatment should be combined %ith iodide and propranolol pre.treatment. HYP(RTHYROIDISM DU( TO I*APPROPRIAT( TSH S(CR(TIO* Dormal or even elevated serum T, & in combination %ith clinical hyperthyroidism& and increased serum thyroid hormone levels& may be seen in the presence of a T, secretin$ pituitary tumor or selective partial pituitary resistance to thyroid hormone. S(,(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. ,ince the pituitary is selectively resistant to thyroid hormone& the set.point of the pituitary& i.e. the specific T, E thyroid hormone ratio needed to ensure normal thyroid $land activation& is set at a hi$her level of serum thyroid hormone concentration. The other body tissues appear more sensitive to thyroid hormones& and the clinical picture of thyroto"icosis develops. Cye symptoms and other characteristics specific for *raves! disease are absent. This syndrome may be inherited in an autosomal dominant mode. ,ince there is no pituitary tumor& the ratio of T, alpha.subunits to total T, is less than 1& %hereas in a T, producin$ pituitary tumor (see belo%) this ratio is usually above 1. HYP(RTHYROIDISM DU( TO A TSH S(CR(TI*) PITUITARY AD(*OMA yperthyroidism due to a T, secretin$ pituitary tumor is rare. /n 11<# Tolis et al. (153) revie%ed the literature and found that bet%een 15 . -5 patients had been reported. /n 11#3 another revie% found 1< %omen and 16 men %ith hyperthyroidism due to a T, producin$ pituitary tumor (154) The criteria that are re0uired to confirm this entity are the follo%in$. The patient is clinically thyroto"ic %hile serum levels of free T4 and7or free T3 are elevated and serum T, concentration is normal or increased. FisualiAation of the pituitary by ma$netic resonance ima$in$ sho%s a pituitary tumor. The concentration of T, alpha .subunits in blood is above normal& as is the ratio of T, alpha 7T, (154a). (ituitary T, adenoma produce normal forms of T, 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.- years1(56) ,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. 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<). ?hen the dia$nosis is established& patients should have treatment of the pituitary tumor. This usually consists of sur$ery plus e"ternal radiation. This approach ho%ever is not al%ays successful (15<). A relapse %as seen in 4 of 5 operated and postoperatively irradiated patients durin$ follo%.up of 3.5 . 6 years. Another report (15#) described a relapse in all 4 similarly treated patients. ?hen the tumor is a macroadenoma& its behavior tends to be a$$ressive. The pro$nosis is better in patients %ith microadenomas(156). 8etter results %ith macroadenomas %ere reported by ,mallrid$e and ,mith (154). All patients had lar$e adenomas. Ci$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. DormaliAation of the elevated biolo$ic to immunolo$ic ratio of serum T, after operation points to successful treatment of the adenoma (156). 3rom these results a combination therapy consistin$ of sur$ery and irradiation seems imperative& at least in T, .producin$ macroadenomas. As these tumors may become invasive early treatment is advised.

Administration of dopamine a$onists or of somatostatin analo$ues are useful to shrin) the tumor and in sur$ical failures (154a&151.113). The slo% release formulation of the somatostatin analo$ lanreotide has recently been used in treatin$ a series of 1# patients %ith pituitary thyrotropin secretin$ adenomas %hich had induced hyperthyroidism. /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. There %as no si$nificant chan$e in adenoma siAe. The lanreotide in this formulation appears to be an effective medical therapy for T, .secretin$ adenomas. (113a) 9on$ term treatment %ith lanreotide and caber$oline has also been successful (113b). CO*)(*ITA, HYP(RTHYROIDISM Autosomal dominantly inherited non.autoimmune hyperthyroidism %as ori$inally described by +upreA et al (114). /n - )indred!s activatin$ $ermline mutations& Fal 551 Ala and Cys 6<- Tyr respectively& involvin$ the third and seventh transmembrane se$ment of the thyrotropin receptor& %ere found. A third mutation ((he 631 9eu) %as described in a similar patient %ith con$enital hyperthyroidism (114a). ,ince this %as not found in parental +DA& it represented a neo mutation. 114b ?hen mutant receptor $ene constructs %ere transfected into CO, cells& constitutive cA4( accumulation %as observed (114&114a). ,everal other $ain of function mutations have been reco$niAed& all localiAed in e"on 15 %hich encodes for the entire trans.membrane re$ion of the T, receptor. =ecently a $ermline mutations in the e"tra.cellular portion of the T, receptor %ere found to cause con$enital hyperthyroidism (114b&114c). /t is note%orthy that similar& but somatic& mutations are found in to"ic adenoma tissue (see section 'to"ic adenoma' this chapter). The syndrome is fully discussed in Chapter 16a. )(STATIO*A, HYP(RTHYROIDISM This rare syndrome consists of hyperthyroidism induced by pre$nancy. /t is caused by a mutation in the T, receptor renderin$ it also specific for human C*(114d). ,ee chapter16a. THYROTOXICOSIS DU( TO M(TASTATIC THYROID CARCI*OMA /n rare situations metastatic follicular carcinoma may cause thyroto"icosis. Accordin$ to Chrenheim et al (115)& 9eiter et al. %as the first to describe& in 1146& thyroto"icosis due to functionin$ metastases in a patient %ith adenocarcinoma of the thyroid. Chrenheim et al. reported -5 similar cases& and recently 54 cases reported in the literature %ere analyAed (115a). The a$e and se" distribution in such patients is no different from that of other patients %ith follicular carcinoma& but %ithout thyroto"icosis. About #5; of patients are older than 45 years and the femaleE male ratio is 3E 1. The clinical picture of thyroto"icosis is similar to the $eneral symptoms of other causes of thyroto"icosis. 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). 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<). Other abnormalities may ho%ever be present in the complicated process of thyroid hormone synthesis in carcinomatous tissue. 3or instance& there is evidence that e"pression of the T, 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, & and normal or lo% serum T4 (116&11<&111). :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 $land is still present. The metastatic pattern of this type of adenocarcinoma is as is usually found in thyroid adenocarcinoma patients& that is predominantly in bone& lun$ and mediastinum. Treatment of metastatic functionin$ thyroid carcinoma consists of administration of radioactive iodine. The usual dose ran$es bet%een 3<55 . <455 480 (155.-55 mCi). C"acerbation of

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. /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. *raves! disease and follicular carcinoma occasionally co.occur& and this may not be a coincidence (1-1.1-3). There may be an association bet%een *raves! disease and thyroid carcinoma& possibly because of lon$standin$ thyroid stimulation by immuno$lobulins (1-4). Althou$h it has been postulated that thyroid carcinoma in patients %ith *raves! disease behaves more a$$ressively (1-5)& this is uncertain (1-6). STRUMA O<ARII ,truma ovarii is a rare tumor occurrin$ in a teratoma or dermoid in the ovary. /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-#). Ovarian strumal carcinoid tumors have been found to synthesiAe different peptide hormones includin$ calcitonin& ACT & ,=/3& neuron.specific enolase& chromo$ranin& synaptophysin& serotonin and other peptides (1-<.1-1). ,truma ovarii is unilaterally localiAed in about 15; of patients and about #5; are beni$n (135). (ardo.4indan and FaA0ueA (131) revie%ed the %orld literature on mali$nant struma ovarii until 11#3& findin$ only 1# cases. As differentiation bet%een carcinoid and struma tissue is sometimes difficult& electron microscopic studies in combination %ith specific immunochemistry may be necessary. ,truma ovarii seldom causes hyperthyroidism. /n thyroto"icosis due to struma ovarii& upta)e of radioactive iodine of the thyroid $land is lo% in the presence of elevated serum thyroid hormones and suppressed T, . :pta)e of radioactive iodine over the ovarian tumor confirms the dia$nosis (131a&b). 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-). (ossibly this could represent the effect of thyroid stimulatin$ antibodies on both tissues. Treatment of struma ovarii& either %ith euthyroidism or thyroto"icosis& should be effected by removal of the ovarian tumor. /n the case of co.e"istent thyroto"icosis& preparation for sur$ery should be done by administration of antithyroid dru$s& sometimes in combination %ith beta.bloc)in$ a$ents. 8ecause of the co.e"istin$ teratoma& it is sometimes difficult to determine if the thyroid tissue in the tumor is beni$n or mali$nant. /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 $rounds& and secondly because of the un)no%n radiation effects on the other elements of the teratoma. +oppler flo% may aid in the preoperative dia$nosis of struma ovarii. 8lood flo% si$nals& detected from the center of the echoic lesion& and lo% resistance to flo% may be more common in struma ovarii (13-a). =ecently a rare case of thyroto"icosis %as described in a <3 year old %omen caused by a to"ic adenoma of the thyroid and an hyperthyroid struma ovarii (13-b) SUMMARY Thyroto"icosis arises from several etiolo$ies other than *raves! disease. To"ic adenomas are characteriAed by a sin$le hyperactive nodule in the thyroid leadin$ to clinical and biochemical thyroto"icosis. Autonomous or to"ic adenomas are considered to ori$inate from somatic mutations in the $ene of *salpha protein or the $ene of the thyrotropin receptor. /n to"ic adenoma only a hot nodule is visible on the thyroid scan. The fre0uency of to"ic nodules varies in different countries. The fre0uency of to"ic adenoma in patients %ith hyperthyroidism ran$es bet%een 1.5 and 44.5; as reported from different surveys. The possibility of developin$ thyroto"icosis in a patient %ith a hot nodule %ith a diameter of 3 cm or lar$er is -5; in 6 years. This ris) is substantially less in smaller nodules. Also& older patients %ith a hot nodule are more li)ely to become to"ic as compared to youn$er patients. +efinitive treatment consists of sur$ical

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

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