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Management of the Nontoxic Multinodular Goiter: A North American Survey

Department of Endocrinology, Odense University Hospital (S.J.B., F.N.B., L.H.), DK-5000 Odense C, Denmark; and Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine (P.W.L.), Baltimore, Maryland 21287-4904

Address all correspondence and requests for reprints to: Steen J. Bonnema, M.D., Department of Endocrinology M, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: steen.bonnema{at}dadlnet.dk

	Abstract

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To assess approaches to the diagnosis and therapy of patients with nontoxic multinodular goiter, a questionnaire was circulated to all members of the American Thyroid Association (ATA). An index case report was presented (42-yr-old woman with an irregular, nontender, bilaterally enlarged thyroid of 50–80 g and no clinical suspicion of malignancy or thyroid dysfunction), and 11 variations were proposed to evaluate how each alteration would affect management. One hundred and forty responses were retained (50% of clinically active ATA members). For the index case, a TSH determination was the routine choice of 100%, and serum thyroid autoantibodies were measured by 74%. Simultaneous use of serum TSH, a thyroid hormone assay, and antithyroid peroxidase was employed by 49%. Only 4% included a calcitonin assay. The median number of blood tests ordered was 3 (range, 1–7). Ultrasound was used by 59%, thyroid scintigraphy by 24%, and both imaging modalities by 11%. Fine needle aspiration biopsy (FNAB) was performed by 74%. If scintigraphy showed inhomogeneous tracer distribution or a dominant hypofunctioning region, FNAB was performed by 15% and 97%, respectively. L-T₄ treatment was preferred by 56%, radioiodine by 1%, surgery by 6%, and 36% would recommend no treatment. A large goiter, a history of external radiation, or rapid growth increased the preference for surgery. In case of a suppressed serum TSH level, radioiodine was used by 56%. In conclusion, in the work-up of patients with nontoxic multinodular goiter, ATA clinicians employ determinations of TSH often combined with a T₄ and/or T₃ assay and antithyroid peroxidase antibodies. Thyroid imaging, primarily ultrasound, is performed by more than two thirds, and FNAB by three fourths. This diagnostic evaluation is significantly less extensive than that of the European Thyroid Association members, but the distribution of treatment choices is quite similar. In accordance with their European colleagues, the majority of ATA members prefer the use of L-T₄ therapy. There is, however, still a wide variation in the perceived optimal management of this condition among members of both organizations.

	Introduction

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WHAT SHOULD BE the optimum approach to the patient with a nontoxic multinodular goiter? Far from every clinical initiative is evidence based, and there are few well conducted clinical trials in this field. To elucidate prevailing trends in the diagnosis and treatment of nodular thyroid diseases, we previously performed and published three international surveys describing the management of the solitary thyroid nodule in Europe (1) and North America (2), and that of the nontoxic multinodular goiter in Europe (3). They all revealed significant variations and regional preferences among thyroidologists managing these conditions. We have now examined the approach to nontoxic multinodular goiter by clinicians in North America and compared them with the previous European survey (3) on this topic.

	Materials and Methods

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Methods and structure of the questionnaire

The questionnaire was distributed to all North American members of the American Thyroid Association (ATA) in December 1999, with two subsequent reminders to nonresponders. The questionnaire was based on the following case: "a 42-yr-old premenopausal Caucasian woman admitted to your hospital/clinic due to an irregular nontender bilaterally enlarged thyroid; clinically judged to be 50–80 g, absence of lymphadenopathy; no family history of thyroid disease; no previous external irradiation; no symptoms of thyroid dysfunction or anterior neck pain; the goiter has been present for 3–5 yr, and the patient reports moderate local neck discomfort." The survey then asked questions related to the diagnostic investigations (in vitro and in vivo tests) and choice of therapy. In the second part of the questionnaire, 11 variations of the initial case report were listed, with only one variable changed in each case (shown in Fig. 1). The clinicians were asked to indicate for each variation whether the management plan was changed and, if this was the case, the alterations in the diagnostic and therapeutic procedures. Except for a few minor linguistic modifications, the questionnaire was the same as that used for the corresponding European survey (3) on the same topic.

View larger version (42K): [in this window] [in a new window]   Figure 1. Clinical variations (no. 1–11) in the questionnaire are listed. A, The distribution of the various treatments is given for the index case and each clinical variation. PEIT, Percutaneous ethanol injection therapy. B, Percentage of the respondents changing their management (altered diagnostic or treatment strategy) for each of the variations.

All data were registered in a computer-operated database (MS-office Excel 2000), and the statistical software used was WINKS 4.6 (TexaSoft, Cedar Hill, TX). Results are predominantly given as frequencies. McNemar’s test was employed to analyze an altered attitude compared with the basic standpoint in the index case. The ² test (or Fisher’s exact test) was used to test for differences between groups and also to compare the results from the present study with those from the European Thyroid Association (ETA) survey. P < 0.05 was considered significant.

	Results

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Survey response and characteristics of respondents

The questionnaire was initially circulated to 326 North American clinician members of the ATA. Fifty-six members proved to be either retired or were no longer seeing such patients. From the remaining 270 eligible clinicians, 142 responses were received, of which 2 questionnaires were not completed sufficiently and therefore were disregarded. Thirty-three responses originated from clinicians working together within teams comprising 2–7 persons. All together, 132 responses from 25 states in the U.S. (94.3%) and 8 responses from Canada (5.7%) were retained for analysis (response rate, 51.9%). One-hundred twenty-eight clinicians were specialists in endocrinology (91.4%), 5 were specialists in nuclear medicine (3.6%), and 7 were specialists in surgery (5.0%). Twenty-eight percent had diagnosed and treated more than 50 patients with multinodular goiter within the previous 6 months.

In vitro diagnostic procedures in the index case (Table 1)

The index patient was investigated as an out-patient by all respondents. A TSH determination was the routine choice of 100%. A total and/or free T₄ (T₃) assay was included by 68.6% (33.6%) of the clinicians. One or more serum thyroid autoantibodies were measured by 74.3% (antithyroid peroxidase, 61.4%; antimicrosomal, 17.1%; anti-Tg, 34.3%). Only 3.6% included a calcitonin assay. The median number of blood tests used was three (range, one to seven). Serum TSH as the only biochemical test was preferred by 15.7%, two or three tests were preferred by 35.7%, four or five tests were preferred by 44.3%, and 4.3% of the respondents would use six or more tests. Simultaneous use of serum TSH, a thyroid hormone assay (T₃ and/or T₄), and antithyroid peroxidase was a common combination, employed by 49.3%.

In vivo diagnostic procedures in the index case (Table 2)

Either thyroid scintigraphy or ultrasound (US) was used by 71.4% of the clinicians, and 11.4% would employ both techniques. US was preferred to scintigraphy (59.3% vs. 23.6%). Other details are listed in Table 2. In case ultrasound was used, size determination was applied by 68%, morphology (Gray scale) by 58%, and Doppler by 19%. The isotopes used for scintigraphy were ¹²³I (49%), ^99mTc (42%), and ¹³¹I (9%). X-Ray of the trachea/thorax was suggested by 12.1% of the respondents, and a computed tomography/mass spectrometry scan of the neck was suggested by 7.9%. Ten percent would perform a flow-volume loop assessment, whereas 2.9% would add an x-ray with barium ingestion to the diagnostic set-up.

Treatment in the index case (Table 3)

The majority (56.4%) of the respondents would advocate the use of L-T₄ therapy. Details of L-T₄ therapy are listed in Table 3. A slightly suppressed serum TSH level between 0.1 and 0.3 mU/liter was regarded as the optimum target among 76% of the clinicians. The use of L-T₄ therapy continuously for several years or indefinitely was recommended by 42%. To monitor the effect of L-T₄, US scan was used by 38%. Radioiodine therapy was recommended by only 2 clinicians (1.4%). In both cases, the orally administered dose calculation included thyroid volume and an uptake measurement. Surgery was chosen by only 6.4% of the respondents. A near-total thyroidectomy was the preferred method. We asked whether the postoperative use of L-T₄ in the euthyroid patient was recommended. By including data from all 11 variations of the index case to obtain valid information on this topic, 53.6% answered this question affirmatively. More than a third (35.7%) refrained from any therapy. Almost all of these clinicians, however, would still follow the patient in their own clinic.

Regional differences were analyzed for Canada and five states (New York, Minnesota, Michigan, Massachusetts, and California) from which at least eight responses were received. No substantial differences between these regions were found with regard to biochemical measurements. In Michigan a scintigraphy was ordered by 75%, in most cases as the only imaging method, whereas this method was used by less than 25% elsewhere. US was also relatively infrequently used in Massachusetts (27%). In New York and Canada, US was used by more than 50% for guidance of FNAB, whereas the majority of clinicians in the other regions did not use US guidance. Regarding therapy, clinicians in New York preferred L-T₄ (81%), whereas 91% and 75% in Minnesota and Canada, respectively, favored no treatment.

Clinical variations: altered management (Table 4 and Fig. 1)

A suppressed serum TSH had the greatest impact regarding a change in management, as 95.7% of the respondents would change their evaluation or treatment of the patient compared with the index case. This also applied for the majority of the respondents in case of rapid growth (77.9%), a large thyroid (68.6%), a history of radiation of head/neck (66.4%), and a family history of thyroid cancer (65.0%; Fig. 1B). In Table 4 those variations are shown that caused the clinicians to ask for additional specific tests/examinations not ordered initially. Thus, if not performed in the index case, a suppressed serum TSH prompted many clinicians to perform scintigraphy and an uptake measurement. Calcitonin would additionally be determined by 44.3% in the case of a family history of thyroid cancer. Although employed by many clinicians in the index case, a further 10–20% would use FNAB if malignancy could be suspected (family history of thyroid cancer, history of radiation of head/neck, rapid growth). Figure 1A shows the distribution of the five different treatment strategies in question for each clinical variation. If TSH was suppressed, radioiodine would completely replace L-T₄ and was the prevailing therapy recommended by 56.4%. Compared with the index case, radioiodine was also slightly more used in intrathoracically located (5.7%) or large goiters (8.6%) as well as in elderly patients (8.6%). In the latter case, fewer would use L-T₄, which was, however, still preferred by 33.6%. Surgery was the favored choice in several variations and was recommended by the majority in case of rapid growth or a large thyroid. When faced with a predominantly cystic nodule, needle aspiration and/or percutaneous ethanol injection therapy would be performed by 7.9% of the clinicians. Regarding a shift in strategy from an initially destructive therapy, i.e. surgery or radioiodine, to a more conservative strategy and vice versa, seven variations had a statistically significant impact on this choice (no. 1 and 5–9, P < 0.001; no. 3, P < 0.05).

Comparison with ETA survey (Tables 1, 2, and 5)

Generally, European thyroidologists use a more extensive diagnostic evaluation, particularly with regard to measurement of serum calcitonin, which is preferred by nearly a third of ETA members in the index case (Table 1). Europeans also often use thyroid scintigraphy and ultrasound simultaneously, while North Americans are much more selective (Table 2). This difference is most pronounced for the use of scintigraphy. Although members of both ETA and ATA disagree on the choice of treatment in the index case, the distribution of treatment preferences do not differ between the two organizations (Table 5). There are, however, differences. In some of the variations, surgery is more frequently recommended in Europe, and aspiration and/or percutaneous ethanol injection are preferred if the goiter is dominated by a cystic nodule.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Several national and international surveys have previously compared regional preferences in the management of Graves’ disease and demonstrated marked differences of opinion, particularly relating to treatment (9). More recently, nodular thyroid diseases have been subject to similar surveys (1, 2, 3), and the present study is the first to summarize the strategies in North America for the management of nontoxic multinodular goiter. Similar to what we obtained in our recent ATA questionnaire study on the solitary nodule (2), the response rate is only slightly above 50% of the target group within the ATA despite great efforts to maximize the participation by two reminders to nonresponders. However, the absolute number of respondents is higher than in the corresponding ETA survey (140 vs. 120) (3). Also, it is evident that many patients suffering from multinodular goiter are managed, in hospital units as well as in primary care, by physicians not organized within the ATA. Nevertheless, being aware of these limitations, we regard the results of this survey to reflect the current trends among North American experts within this field.

The diagnostic evaluation of multinodular goiter patients by North American clinicians is less extensive than in Europe (1, 3), as was apparent in the previous ATA survey (2). The reason for this discrepancy may reflect the sparseness of well conducted trials within this field, leaving the diagnostic evaluation and treatment strategy to local traditions and what is feasible at the local institution. Differences in the availability and cost of the various biochemical tests as well as the accessibility of the imaging methods and treatment options without a doubt play a significant role in this setting. Thus, the more frequent use of computed tomography/mass spectrometry scan in North America, contrasting the trend otherwise seen in the diagnostic set-up, probably reflects this equipment being more propagated on this continent. The use of serum calcitonin is particularly less commonly used by ATA members unless there is a family history of thyroid cancer, in accordance with existing guidelines (10). Routine use of serum calcitonin in nodular thyroid disease has been debated in several papers (11, 12, 13) and has recently found support in the study by Hahm et al. (14). After serum TSH measurement, FNAB is the diagnostic test most often employed (74% of the respondents). This is similar to the previous survey on evaluation of solitary thyroid nodules (2). In Europe, biopsy is more likely to be performed after scintigraphy shows a dominant cold nodule (3), whereas this imaging method is used by less than one in four ATA members. The usefulness of FNAB to exclude thyroid malignancy no doubt depends on the cytopathological expertise available, which may explain this difference in its utilization (15, 16). In this context, US guidance was preferred by two thirds of the respondents, presumably to reduce the risk of sampling error (17).

Among North American as well as European clinicians, there is disagreement on treatment recommendations. One third of the respondents would advise observation in the index case. However, L-T₄ is the therapy used by 56%. This is despite a lack of evidence from prospective clinical trials demonstrating the value of L-T₄ treatment for this condition. Berghout et al. (4) in a randomized, controlled trial showed that only 58% of the patients responded to this therapy at 9 months with a mean reduction in goiter volume of 25% compared with the response to placebo. In another recently published trial (18), L-T₄ produced goiter reduction in only 1% of patients vs. 44% responders in a radioiodine-treated group. Furthermore, thyrotoxic symptoms emerged in more than one third of L-T₄-treated patients, and significant bone mineral loss was also demonstrated with L-T₄ therapy. Three quarters of the respondents who recommended L-T₄ therapy considered a serum TSH level between 0.1–0.3 mU/liter as the appropriate target.

Unless the patient’s serum TSH level was suppressed, which resulted in a marked shift in treatment strategy toward radioiodine therapy, ATA members were reluctant to use radioiodine. This is despite the fact that radioiodine therapy has been shown to be highly useful for goiter reduction in nontoxic (18, 19) as well as in toxic multinodular goiter (20), producing a 40–60% shrinkage in volume within 2 yr. North American, like European (3), clinicians may be influenced more by the reported side-effects of radioiodine therapy, including hypothyroidism in 20–45% of patients within the first year (18, 19), rare cases of radiation thyroiditis (21), and the potential induction of Graves’ disease (21).

Many North American clinicians turn to surgery in the case of a large goiter or factors raising suspicion of malignancy. Their European colleagues seem to be even more prone to surgery in some of these situations. The more conservative strategy among ATA members is perhaps founded on the fact that the goiter frequently recurs, with or without postoperative use of L-T₄, during a long-term postoperative follow-up (22). It is remarkable that in the elderly patient also, who is known to be at higher risk of atrial fibrillation and osteoporosis, one third of the ATA members, twice as many as in Europe, still prefer L-T₄ therapy. Faced with a cystic nodule, aspiration or percutaneous ethanol injection therapy is not much used in North America, in contrast to the widespread application of this technique in Europe.

In conclusion, serum TSH, fine needle biopsy, and, less frequently, US are the cornerstones of the diagnostic evaluation for patients with nontoxic multinodular goiter in North America. The strategy is significantly more conservative in resource utilization than in Europe. Although a trial of L-T₄ therapy is preferred by members of both the ATA and ETA, there is limited evidence of its efficacy in the majority of patients. Radioiodine treatment is less commonly considered for treatment of nodular goiter in North America unless chemical evidence of subclinical thyrotoxicosis is present. Considerable disagreement among thyroidologists remains regarding ideal management of this condition.

	Acknowledgments

 
We thank all members of the American Thyroid Association, who contributed to the study by answering the questionnaire. Permission to include data from the previously published ETA survey was kindly given by Blackwell Science Ltd.

	Footnotes

 
This work was supported by grants from the Agnes and Knut Mørk Foundation. The results were presented in part at the 73rd Annual Meeting of the ATA, Washington, D.C., November 7–10, 2001.

Abbreviations: ATA, American Thyroid Association; ETA, European Thyroid Association; FNAB, fine needle aspiration biopsy; US, ultrasound.

Received July 3, 2001.

Accepted October 8, 2001.

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