Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

25.Toxic Adenoma and Toxic Multinodular Goiter

Dagmar Führer

Knut Krohn

Ralf Paschke

Toxic adenoma (TA) and toxic multinodular goiter (TMNG) constitute the important clinical presentations of thyroid autonomy, a condition where thyrocytes function and produce thyroid hormones independently of thyrotropin (TSH) and in the absence of TSH-receptor stimulating antibodies. The autonomous secretion of thyroid hormones leads to TSH suppression and quiescence in the nonautonomous thyroid tissue and can ultimately result in thyrotoxicosis (hence, the notion “toxic”).

Constitutive activation of the guanine (G) nucleotide-binding protein–coupled TSH receptor (TSH-R), or, less frequently, the α subunit of the G protein by somatic mutations in their respective genes, has been identified as the predominant molecular causes of thyroid autonomy (1,2).

TA is a clinical term referring to a solitary autonomously functioning thyroid nodule that produces thyroid hormones in excess. The autonomous properties of TA are readily evidenced on radioiodine or technetium (99mTc) imaging, whereby the classical appearance is that of circumscribed increased uptake with suppression of uptake in the surrounding extranodular tissue (“hot” nodule, Fig. 25.1).

FIGURE 25.1. Technetium scintiscan of a toxic thyroid adenoma. Molecular analysis of genomic DNA extracted from the adenoma tissue shows a heterozygous TSH receptor point mutation (exchange of valine for alanine in codon 623; A623V). In contrast, only the wild-type TSH-receptor sequence is present in the surrounding normal thyroid tissue.

TMNG is a heterogeneous clinical disorder characterized by the presence of autonomously functioning thyroid nodules (AFTN) in a goiter with or without additional nodules. These additional nodules can show normal or decreased uptake (cold nodules) on scintiscan. Thus, in TMNG the variable scintigraphic pattern includes circumscript areas of increased uptake with suppression of the surrounding thyroid tissue or an uneven (patchy) increase in uptake combined with areas of decreased and/or normal uptake. TMNG comprises the most frequent form of thyroid autonomy (see Chapter 68).


The prevalence of thyroid autonomy is inversely correlated with the population's iodine intake. Thus, thyroid autonomy is a common finding in iodine-deficient areas, where it accounts for up to 60% of cases of thyrotoxicosis (TA, ~10%; TMNG, ~50), (3,4). Several studies have suggested that TMNG mostly originates from euthyroid goiters, and scintigraphically nonsuppressible foci corresponding to autonomous thyroid tissue have been demonstrated in up to 40% of euthyroid patients with goiters in iodine-deficient areas (5,6). Furthermore, the prevalence of thyroid autonomy correlates with increased thyroid nodularity and increases with age (3,7,8). In contrast, thyroid autonomy is rare (3% to 10% of cases of thyrotoxicosis) in regions with sufficient iodine supply (3,9). Correction of iodine deficiency in a population results in a decrease of thyroid autonomy. An impressive 73% reduction in prevalence of TMNG only 15 years after the doubling of iodine content of salt has been observed in Switzerland (4,10). The precise molecular mechanisms linking iodine deficiency and thyroid autonomy are not known. However, in vitro, iodine deficiency has been shown to result in impaired thyroid hormone production and may cause a compensatory increase in thyroid cell mass (for review, see reference 2). Smoking has been identified as another environmental risk factor for TMNG in women (10a,36). While Graves' disease prevails in young people with thyrotoxicosis, TMNG tends to occur in older age groups (7,11). As with all thyroid diseases, TA and TMNG are more frequent in women (~4 to 10:1) (11,12), and a thyroid growth promoting effect of estrogen described in vitro in rat FRTL-5 cells and thyroid cancer cell lines has been proposed as a possible contributing, constitutional effect of gender (13,14).


Clinical features in a patient with thyroid autonomy can be attributed to (a) symptoms of thyrotoxicosis and (b) the nodule(s) or, if present, goiter.

The clinical presentation of thyrotoxicosis varies with age, and in the elderly it is is often oligosymptomatic (12,15).

In a series of 84 French patients with overt thyrotoxicosis, atrial fibrillation and anorexia dominated in the older age group (≥70 years), while classical signs of thyrotoxicosis, e.g., nervousness, weight loss despite increased appetite, palpitations, tremor, and heat intolerance were more frequently observed in younger patients (≤50 years) (16). Alternatively, a patient may present with a lump or disfigurement of the neck, intolerance of a tight collar, or increase in collar size. Dysphagia or breathing difficulties due to esophageal or tracheal compression may be apparent, especially with large TMNG (12) (see Chapter 69).

Subclinical thyrotoxicosis, defined by low or suppressed serum TSH with normal free thyroxine (T4) and free triigdothyronine (T3) levels is more commonly observed in older patients with TMNG (17). Moreover, the incidental finding of low or suppressed TSH levels on routine investigation for other indications is frequently the first evidence for the presence of thyroid autonomy, particularly in regions with iodine deficiency. Subclinical thyrotoxicosis is more than “just” a low TSH status, since it is associated with atrial fibrillation and a reduction in bone density (17). In addition, an increased cardiovascular mortality rate in patients with low serum TSH levels has recently been described in a 10-year cohort study in the United Kingdom (18).

Very rarely thyroid autonomy occurs in conjunction with autosomal dominantly inherited nonautoimmune hyperthyroidism caused by activating germline mutations in the TSH-R gene (1). Clinical characteristics comprise the presence of thyrotoxicosis and goiter in at least two generations with absence of typical diagnostic features of Graves' disease, e.g., thyroid eye disease and TSH-receptor (TSH-R) antibodies. Furthermore, once antithyroid treatment has been stopped or after partial thyroidectomy, thyrotoxicosis will recur in all patients with activating TSH-R germline mutations. Lastly, persisting neonatal thyrotoxicosis and unusual relapsing nonautoimmune thyrotoxicosis in childhood are highly suggestive of the condition irrespective of a positive family history. So far, more than 150 patients (10 families and 11 children with sporadic occurrence of TSH-R germline mutations) have been reported in the literature (18a). Thyroid ablation is advocated as first-line treatment (surgery and/or radioiodine) for preventing relapses. Molecular analysis for germline TSH-R mutations offers the possibility for family screening, preclinical diagnosis, and genetic counseling (1,19).


Diagnosis of thyroid autonomy is based on three characteristics:

1. Confirmation of clinically suspected thyrotoxicosis by an abnormal thyroid function test. Typically, there is overt thyrotoxicosis (low TSH, high free thyroid hormones). However, dependent on the autonomous cell mass, subclinical thyrotoxicosis (TSH low, free T3 and free T4 normal), or even euthyroidism may be found.

2. Presence of palpable or sonographic nodule(s).

3. Increased radionuclide uptake in the nodule(s) concomitant with a decreased uptake in the surrounding extranodular thyroid tissue (Fig. 25.1). The most commonly used isotopes are 99mTc and 123I, both of which are transported into the thyrocytes by the sodium-iodide symporter (NIS), but only 123I is organified. Several studies have revealed a comparable diagnostic value of the two isotopes. The advantages of 99mTc, which is more frequently used in Europe, are its short half-life (6 hours) and low cost (20,21).

If thyroid autonomy is suspected in a euthyroid patient, a “suppression” scan can be performed after administration of thyroid hormone (i.e., 75 µg/day T4 for 2 weeks followed by 150 µg/day for 2 weeks), after which uptake in all nonautonomous tissue will be suppressed and thyroid autonomy is unmasked (5).

Measurement of thyroid autoantibodies is not routinely performed in thyroid autonomy. However, in iodine-deficient areas, distinction between Graves' disease and TMNG can be difficult if extrathyroidal manifestations of the former are absent and diagnostic findings are “atypical,” e.g., presence of thyroid nodules (~27% to 34% by ultrasonography) in suspected Graves' disease patients and patchy rather than diffuse uptake on scintiscan (22,23). In these conditions, determination of TSH-R antibodies is helpful to establish the correct diagnosis (23,24). Urinary iodine excretion can be measured in case of suspected iodine contamination (11). Computed tomography (CT) and magnetic resonance imaging techniques are not routinely indicated for diagnosis of thyroid autonomy, but may be used for presurgical planning in patients with large and partly intrathoracic goiters (12).


According to World Health Organization criteria, toxic thyroid nodules can be histologically classified as encapsulated follicular neoplasm (true adenoma) or adenomatous nodules, which lack a capsule (25). In addition, secondary changes such as hemorrhage, calcification or cystic degeneration is frequently observed.

In vivo characteristics of TA have been described in detail (26). Increased iodide uptake, thyroid peroxidase messenger (mRNA), and protein content, as well as increased thyroid hormone secretion, which could be further stimulated by TSH, were observed in a series of 51 toxic nodules. Up-regulation of NIS and pendrin contributing to the augmented iodine-trapping characteristics of TA have been reported by other investigators (27). Basal inositol phosphate generation was not found to be increased in toxic thyroid nodules, compatible with a predominant constitutive activation of the cyclic adenosine monophosphate (cyclic AMP)–protein kinase A cascade through TSHR or Gsα protein mutations in TA and TMNG (26). Stimulation of growth has been investigated in TA using the proliferation markers Ki67 and PCNA (26,28). However, the increase in the proliferation index in TA was found to be relatively low (two- to threefold) compared to the surrounding normal thyroid. These data are in agreement with the slow course in TA and TMNG; however, they are difficult to reconcile with the evolution of a macroscopic TA from a single mutated cell (estimated number of 30 cell divisions to yield a nodule volume of ~1 mL) (2,29) and thus may more likely reflect the end-stage rather than the initiation of disease (see also etiology of TA and TMNG).

Thyroid autonomy is widely viewed as an almost exclusively benign disease, and there is little evidence in the literature to suggest the contrary. Detailed pathological analyses of reported “toxic thyroid cancer” cases (0.7% to 6% in different series) have shown that, if classified correctly, the cancer (a) usually occurred coincidentally within the same or even in the contralateral thyroid lobe, (b) mostly represented a microcancer (< 1 cm), and (c) was exceedingly rarely located within the hot nodule itself (12,30).


Long-term studies on patients with TA have shown that the natural course tends to be slow. Sandrock et al (31) reported an overall 4.1% annual incidence of thyrotoxicosis in a group of 375 untreated euthyroid TA patients in Germany who were followed for a mean of 53 months. Hamburger (9) highlighted the correlation between nodule size and development of thyrotoxicosis in a group of 349 patients with TA: 93.5% of patients with overt thyrotoxicosis had TA >3 cm in size and patients with a euthyroid TA of >3 cm in size had a 20% risk of developing thyrotoxicosis during a 6-year follow-up period, as opposed to a 2% to 5% risk in patients with nodules < 2.5 cm in size.

Data on progression from euthyroid to subclinical and overt thyrotoxicosis in patients with multinodular goiter are scarce. An incidence of 9% to 10% of overt thyrotoxicosis has been proposed in two studies during a follow-up period of 7 to 12 years (12).

In addition, a sudden increase in TA and TMNG function can be induced by the administration of excessive amounts of iodine, e.g., in the form of contrast media used for angiography and CT scans or by iodine-containing drugs, e.g., amiodarone (32). In the European Study Group of Thyrotoxicosis, iodine contamination was found in 36.8% of patients from iodine-deficient areas with thyrotoxicosis (11). Severity of iodine deficiency, autonomous thyroid cell mass, and older age have been proposed as risk factors for the development of iodine-induced thyrotoxicosis (32).


Lessons from Epidemiological Studies

The results of epidemiological studies outlined earlier in this chapter provided the first evidence that should finally define the etiology of TA and TMNG. Although the picture is far from complete, the most prominent epidemiological factor for the development of TA and TMNG is iodine deficiency (3). Moreover, there is a strong correlation with age, since older patients have a much higher percentage of nodular transformation in iodine-deficient (7,33,34) as well as iodine-sufficient areas (for review, see reference 35). Also, smoking is considered a risk factor for toxic multinodular goiter in women (10a,36). Lastly, TMNG and TA usually develop in an already enlarged thyroid independent of the cause of hyperplasia (for review, see reference 37). These common characteristics indicate that an early stimulus causes enlargement of the thyroid in which the environment for nodular autonomy develops. However, clinical manifestations of TA and TMNG appear only after a long period of time (sometimes up to 30 or more years). In contrast to global activation of thyroid epithelial cell proliferation (e.g., as the result of iodine deficiency), which is the cause of goiter, development of TA and TMNG requires a focal increase of thyroid epithelial cell division. So far, the most common events that lead to tumor growth are somatic mutations.

Somatic Mutations Constitutively Activate the Cyclic Adenosine Monophosphate Cascade

In 1989, Dumont et al suggested molecular defects (e.g., mutations) resulting in signaling through the cyclic AMP cascade as a cause for autonomous function of thyroid epithelial cells (38). Although constitutive activation (independent of a ligand) of the TSHR is now the most prevalent cause of TA and AFTN in TMNG (Fig. 25.2) (1,2,39,40), mutations in the Gsα protein, another element of the cyclic AMP cascade, were detected earlier (41). However, the low frequency of Gsα mutations in benign thyroid tumors started further screening for molecular defects in cyclic AMP-signaling components. Inspired by in vitro mutagenesis studies of the G protein–coupled β-adrenergic receptor (42) the G protein–coupled TSHR was identified as a target of somatic point mutations in TA of the thyroid (43).

FIGURE 25.2. Identification of somatic TSH receptor mutations in “hot” microscopic areas in euthyroid multinodular goiters of iodine deficiency areas (6).

Moreover, the clinical relevance of TSH-R mutations has been demonstrated in the context of germline mutations causing autosomal dominant nonautoimmune thyro toxicosis (1). Highly variable prevalences of TSH-R mutations in TA (20% to 82%) from regions with similar iodine supply have been reported (reviewed in reference 44). Similarly, the Gsα protein mutation frequency ranges from 8% to 75% (reviewed in reference 45). Most likely, these differences in the frequency of TSH-R or Gsα protein mutations in different studies result from differences in the sensitivity of mutation detection, limited size of the sample, and quality of tissue preservation, as well as from screening only part of the TSH-R (e.g., exon 10). A recent study of solitary TA (46) suggests that a difference of TSH-R mutation frequency between areas of high (e.g., Japan (47), United States) (48) and medium to low iodine intake (e.g., Europe (2,43,44,45)) is less likely. In conclusion, when considering the published data and in our experience, the rate of somatic TSH-R mutations in TA is most likely ~50% (40,44).

To speculate on the etiology of mutation-negative nodules, the clonal origin of thyroid tissue is an important marker. Mutation-negative autonomously functioning thyroid nodules could comprise polyclonal lesions, which do not evolve from a single mutated cell. However, 50% of mutation-negative cases from female patients show a monoclonal origin when tested for X-chromosome inactivation (44,49). This could indicate a mutation in a gene other than the TSH-R or Gsα protein, but does not prove such a mutation because the size of the thyroid that shows a monoclonal pattern according to X-chromosome inactivation is rather large (50). Since constitutive cyclic AMP activation is mandatory for the phenotype of thyroid autonomy (adenoma and thyrotoxicosis) (1), screening of this signal cascade for candidate genes (e.g., other G-protein subunits, adenylyl cyclase, phosphodiesterase, protein kinase A) that cause TA and TMNG is warranted. However, the number of isoforms for each of these components makes systematic screening rather painstaking. Alternatively, overexpression of signaling proteins like the TSH receptor, Gsα subunits, adenylyl cyclases, or downstream effector molecules could be a cause of autonomously functioning thyroid nodules. Currently, expression profiling of signaling proteins using microarray methodology is a promising approach which may contribute to defining the genetic events that cause TA and TMNG (51,52) and might shift attention to other signaling cascades like the transforming growth factor (TGF)-β cascade (53). Alternatively, an altered turnover of TSH-R protein could result in aberrant TSH signaling. However, data concerning the role of arrestins and G protein–coupled receptor kinases (GRKs) in TSH-R desensitization in vitro (54,55) and data of differential expression of these proteins in thyroid tumors that point to increased desensitization of the constitutively activated TSH-R (56,57) do not as yet allow a final conclusion concerning their role in the etiology of TA or TMNG. More likely, regulation of the TSHR desensitization apparatus and of phosphodiesterases in TA (58) might function as an internal feedback loop to constrain constitutive cyclic AMP activation.

From Hyperplastic Growth to Nodular Transformation

From animal models of hyperplasia caused by iodine depletion (59,60,61) we learn that besides an increase in functional activity, a tremendous increase in thyroid cell number occurs. These two events very likely orchestrate a burst of mutation events. Although the enzymatic sequence awaits further characterization (62), functional activity goes along with increased hydrogen peroxide (H2O2) production and free-radical formation (63), which may damage genomic DNA and cause mutations (64). In addition, a higher replication rate will more often prevent mutation repair and increase the mutagenic load of the thyroid, thereby randomly affecting genes crucial for thyrocyte physiology. Mutations that confer a growth advantage (e.g., TSH-R or Gsα protein mutations) could initiate focal growth. Hence, autonomously functioning thyroid nodules are likely to develop from small cell clones that contain advantageous mutations, as shown for the TSH-R in “hot” microscopic regions of euthyroid goiters (Fig. 25.3) (6).

FIGURE 25.3. Spectrum of activating TSH receptor (TSH-R) mutations identified in patients with a toxic adenoma, toxic multinodular goiter or autosomal dominant non-autoimmune thyrotoxicosis. Note that activating TSH-R mutations are predominantly localized in the TSH receptor transmembrane domain (http://www.uni-leipzig.de/innere/TSHR). In addition inactivation of the TSH-R through mutations (yellow triangles) has been identified as a cause of euthyroid or hypothyroid TSH resistance (see also section The Thyrotropin Receptor in Chapter 8).

Sequence of Events

Epidemiological studies, animal models, and molecular/genetic data outline a general theory of nodular transformation. Based on the identification of somatic mutations and the predominant clonal origin of TA, we propose the following sequence of events that lead to thyroid nodular transformation (Fig. 25.4):

1. Goitrogens like iodine deficiency cause diffuse thyroid hyperplasia.

2. In this stage of thyroid hyperplasia, increased proliferation, together with possible DNA damage due to H2O2 action, causes a higher mutational load with a higher number of cells bearing a mutation. Some of these spontaneous mutations confer constitutive activation of the cyclic AMP cascade (e.g., TSH-R and Gsα mutations) that stimulate growth and function.

3. In a proliferating thyroid, growth factor expression [e.g., insulin-like growth factor-1, TGF-β1, or epidernal growth factor (EGF)] is increased.

FIGURE 25.4. Hypothesis for development of thyroid autonomy. The starting point for the development of TMNG or TA is hyperplasia induced by iodine deficiency. Iodine deficiency increases mutagenesis directly (production of H2O2/free radicals) or indirectly (proliferation and increased number of cell divisions). Subsequently, hyperplasia forms cell clones. Some of them contain somatic mutations of the TSH-R leading to TA (dark spots) or contain mutations that lead to dedifferentiation and therefore cold thyroid nodules (2).

As a result, cells divide and form small clones. After increased growth factor expression ceases, small clones with activating mutations will further proliferate if they can achieve self-stimulation by expression of growth factors. They could thus form small foci which will develop into thyroid nodules. As an alternative to the increase of mass, the thyroid might adapt to iodine deficiency without extended hyperplasia (65). Although the mechanism that allows this adaptation is poorly understood, preliminary data from a mouse model suggest an increase of mRNA expression of TSH-RNIS, and TPO in response to iodine deficiency, which might be a sign for increased iodine turnover in the thyroid cell.



Management of thyroid autonomy has been excellently reviewed by Hegedus et al (12), Hermus et al (66), and others (67). Antithyroid drugs, usually in combination with beta-blocking drugs (preferably nonselective propranolol), is the first-line treatment in all patients with overt thyrotoxicosis. Depending on the type of antithyroid drug, an initial dosage of 30 mg/day of methimazole, 40 to 60 mg/ day of carbimazole, or 300 mg/day of propylthiouracil is recommended. Higher dosages are associated with more frequent adverse effects (3% to 12%) and will only result in marginally faster resolution of thyrotoxicosis (12). Furthermore, a trial of low-dose drug therapy (5 to 10 mg methimazole per day) may be justified in selected patients with symptomatic subclinical thyrotoxicosis (17); alternatively, beta-blocking drugs can be used. Monitoring of thyroid function and side effects are described in Chapter 45.

While the purpose of antithyroid drug therapy is to render the patient euthyroid, there is practically no spontaneous resolution of thyroid autonomy. This implies that once thyroid autonomy becomes clinically manifest, definitive treatment is indicated. Elderly patients with severe nonthyroidal illness may be an exception to this rule. However, benefits and risks of such “long-term” drug therapy have to be considered against the very low risk of definitive treatment (12,68,69,70). Three different ablative treatment options are available for TA and TMNG: thyroid surgery, radioiodine treatment, and percutaneous ethanol injection (12,66,67).


The purpose of thyroid surgery is to cure thyrotoxicosis by removing all autonomously functioning thyroid tissue and other macroscopically visible nodular thyroid tissue. The extent of surgery is determined by preoperative ultrasound and importantly intraoperative morphological inspection (68). For TA, hemithyroidectomy is usually adequate. In the case of TMNG, a subtotal, near-total, or total thyroidectomy is indicated (68). The advantages of surgery (removal of all nodular tissue, rapid and permanent resolution of thyrotoxicosis, and definite histological diagnosis) have to be weighed against general (risk of anesthesia, inpatient treatment) and thyroid-specific side effects, the latter of which are largely dependent on the surgeon's training (vocal cord paralysis ~1%, hypoparathyroidism < 1% for an experienced endocrine surgeon) (68,69) (Table 25.1). The incidence of postoperative hypothyroidism depends on the extent of thyroid resection.


Treatment Option




Rapid control of thyrotoxicosis

Inpatient treatment

 Rapid relief of pressure symptoms

Side effects of anesthesia and thyroid surgery

Removal of all nodular tissue ~100% cure rate Definite histology


Outpatient therapy

Slow induction of euthyroidism

 Easy applicability

Variable reduction in volume

 Less effective in large TMNG

Long-term risk of hypothyroidism

Antithyroid Drug

Outpatient therapy effective for short-term

No remission/cure of thyrotoxicosis Side effects 1%–5%

Easy applicability

Frequent follow-up and compliance required

Ethanol injection

Outpatient therapy 

No randomized trials with 131I and surgery

 Only in specialist centers

 Several injections required

 Less effective in large TA/TMNG

TA, toxic adenoma; TMNG, toxic multinodular goiter.

From Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev 2003;24:102; Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998;338:1438; and Ferrari C, Reschini E, Paracchi A. Treatment of the autonomous thyroid nodule: a review. Eur J Endocrinol 1996;135:383, with permission.

While thyroid surgery is usually performed after euthyroidism has been achieved with antithyroid drug treatment, surgery is also advocated in patients with overt thyrotoxicosis who have had adverse side effects of a drug, or in patients with thyrotoxic storm who are refractory. In amiodarone-induced thyrotoxicosis administration of iopanoic acid, an oral iodinated cholecystographic agent, may result in an impressive, rapid control of thyrotoxicosis prior to thyroid surgery (70,71). Nonrandomized studies suggest that early rather than late emergency surgery should be performed in patients with thyrotoxic storm (72) (see also Chapter 43).

Radioiodine Therapy

131I therapy is widely used for treatment of thyroid autonomy and is highly effective in terms of eradicating thyrotoxicosis and reducing thyroid gland volume. The success rate of individually dosed 131I therapy has been reported to range between 85% and 100% in TA and up to 90% in TMNG. An average thyroid and/or nodule volume reduction of ~40% can be anticipated (21,73).

With large goiters (>80 to 100 mL) or suspicion of malignancy, thyroid surgery is recommended. Different protocols have been suggested for 131I therapy in benign thyroid disease. Some investigators prefer to administer a standard dose, e.g., 10 or 20 m (370 to 740 MBq) per thyroid gland, while others apply a certain 131I activity per gram of thyroid tissue (12,66,67). Different algorithms exist for dose calculation, e.g., in Germany 131I dosage is mostly calculated according to the Marinelli formula, which takes into account the maximum 131I uptake as well as the effective half-life determined after administration of an 131I test dose (73,74) (see also Chapters 12 and 45). Advantages of radioiodine are its simplicity and, in many countries, its outpatient-based applicability. Disadvantages are the “time to euthyroidism” period (6 weeks to >3 months) during which drug therapy has to be continued and thyroid function monitored at 3- to 6-week intervals (12,21) (Table 25.1). Radioiodine treatment is contraindicated in pregnancy, and contraception is advocated for at least 6 months after receiving 131I therapy.

Side effects of radioiodine treatment include transient local pain and tenderness. Exacerbation of thyrotoxicosis due to destructive thyroiditis is very rare (12,67). Population-based studies comprising more than 35000 patients treated with 131I have not shown an increased risk of thyroid cancer, leukemia, or other malignancies, reproductive abnormalities, or congenital defects in the offspring, so that 131I therapy can be considered a very safe treatment in adults (75,76,77). However, caution has been raised about 131I safety in children on the basis of the Chernobyl accident epidemiological data (78).

Postradioiodine hypothyroidism in TMNG and TA usually develops insidiously. Prevalence of hypothyroidism depends on the extent of TSH suppression prior to 131I therapy and the protocol applied (21,73), and, importantly, increases with the duration of follow-up. In a series of 2,123 patients with TA and TMNG the occurrence of hypothyroidism was 3% at 1 year, 31% at 8 years, and 64% at 24 years follow-up, resulting in an annual rate of 2.7% (75). These data emphasize the requirement of long-term monitoring of thyroid function in all patients receiving 131I therapy.

Percutaneous Ethanol Injection Treatment

The principle of percutaneous ethanol injection in TA is the induction of a coagulative necrosis of the autonomous tissue by ultrasound-guided injection of 95% ethanol. This is aided by concomitant thrombosis of small vessels, which can be easily monitored by color Doppler ultrasonography (67,79). Ethanol injection has been studied extensively, predominantly in Italy, and in specialized centers has been demonstrated to be a cost-effective treatment of thyroid autonomy with overall cure rates of 68% to 90% (67,79). The success rate clearly depends on nodule size (highly effective in nodules >15 mL, 75% failure rate in nodules >60 mL) and nodule function (almost 100% cure rate in small pretoxic nodules) (79,80). On an average, 4 to 8 separate ethanol injections are required (with one or more injections per treatment) and can be performed on an outpatient basis (67). Side effects include transient local pain that may be severe (up to 90%), hyperpyrexia (up to 8%), transient dysphonia (5%), and hematoma (4%). Potential long-term problems are tissue fibrosis and adhesion to periglandular structures, which may pose a problem in case of future thyroid surgery (81). The major reason ethanol injection is not widely accepted is the lack of randomized trails comparing it with 131I therapy and/or thyroid surgery. Hence, the usual recommendation is that it should be reserved for patients with contraindications to surgery or radioiodine (e.g., old age, severe nonthyroidal illness).

A summary of the advantages and disadvantages of the different treatments for TA and TMNG is shown in Table 25.1.

Cost-Effective Management of Thyroid Autonomy

In times of limited health care budgets, recommendations for the optimal disease management also have to respect economic factors besides the principles of evidence-based medicine. For instance, iodine deficiency–related thyroid problems in Germany have been estimated to cost more than US$1 billion per year (82). Vidal-Trecan et al (83) have recently described a decision analytical model, based on the cost accounting system of 50 nonprofitable Parisian hospitals (inpatient cost) and the national reimbursement schedule of the French Social Security (outpatient costs), to examine the cost effectiveness of different therapeutic options in TA (hemithyroidectomy, radioactive iodine, and lifelong antithyroid drug therapy). In their model, surgery was the


most effective and least costly strategy in a 40-year-old woman with TA (ε1391 for surgery vs. ε2,825 for 131I and ε5760 for long-term drug therapy, followed by 131I in case of adverse drug reaction). However, radioiodine therapy became more favorable if surgical mortality exceeded 0.6% (e.g., in the elderly with an increased likelihood of multimorbidity). Lifelong drug treatment was the preferred and cost-effective treatment in women >85 years of age. Thus, in choosing the appropriate treatment strategy in TA and TMNG several factors (e.g., age, comorbidity, locally available treatment facilities and expertise, and their costs) which likewise may vary locally, must be considered.


The long-term management of TA and TMNG patients is aimed at the detection and adequate treatment of thyroid dysfunction, prevention and detection of novel nodular thyroid disease, and, in the case of surgery, detection and treatment of postsurgical hypoparathyroidism. In case of 131 I therapy, long-term follow-up for development of hypothyroidism is mandatory (75). Furthermore, the solitary (13) iodine-treated nodule often remains palpable and firm (although smaller), and fine-needle aspiration biopsy may reveal suspicious cells secondary to the radiation. T4 with or without iodine is often administered after thyroid surgery to prevent recurrent goiter/thyroid nodules. Although randomized trials are lacking to provide definite evidence that postoperative T4administration is beneficial, unless the patient is hypothyroid, this treatment strategy is inferred by studies treating goiter/nodules with T4 (84). In addition, in iodine-deficient areas iodine supplementation may be appropriate to prevent recurrent nodular thyroid disease.


This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG/Fu 356/1–1 and DFG/ Pa423/10–1), Deutsche Krebshilfe (10–1575-Pa1), and IZKF Leipzig, BMB-F, Interdisciplinary Centre for Clinical Research at the University of Leipzig 9504 (01KS9504, projects B5, B10, B20, and B14).


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