Management of the Nontoxic Multinodular Goiter in Latin America: Comparison with North America and Europe, an Electronic Survey
http://www.100md.com
《临床内分泌与代谢杂志》
Abstract
To assess diagnostic and therapeutic approaches to nontoxic multinodular goiter and to compare them with previously reported American Thyroid Association (ATA) and European Thyroid Association (ETA) surveys, an online questionnaire was distributed to Latin American Thyroid Society (LATS) members. An index case was presented (42-yr-old woman with an enlarged, irregular, nontender, 50- to 80-g thyroid and no clinical suspicion of malignancy or dysfunction), and 11 variations were proposed to evaluate how each alteration would affect management. We obtained 148 responses (response rate, 50%). In the index case, the most used blood tests were TSH (96%), antithyroid peroxidase antibodies (76%), and free T4 (64%); 5% included a calcitonin assay. Nearly 90% would perform ultrasound, and only 16% used scintigraphy. Fine needle biopsy was indicated by 88%, with ultrasound guidance in 75% of times. For treatment, observation was preferred by 39%, surgery by 28%, levothyroxine by 21%, and radioiodine by 7% (60% with recombinant TSH prestimulation). A suppressed TSH level prompted 45% of the respondents to recommend radioiodine, whereas 70–78% indicated surgery in the presence of a large goiter or suspicion of malignancy. In conclusion, no consensus exists concerning the ideal management of nontoxic goiter among LATS members, in agreement with previous ATA and ETA surveys. Levothyroxine therapy is less used by LATS than by ATA or ETA members, and a more aggressive therapeutic strategy is generally preferred by members of LATS and ETA compared with ATA.
Introduction
NONTOXIC MULTINODULAR GOITER is one of the most prevalent thyroid disorders worldwide and sometimes impairs health and well-being. The optimum management of a patient with nontoxic goiter remains controversial, because well designed clinical studies to support the elaboration of guidelines are sparse or nonexistent. Previous studies have revealed trends in the management of nontoxic multinodular goiter in Europe (1), North America (2), and Australia (3), showing significant variations and regional preferences among thyroidologists. We conducted this survey among members of the Latin American Thyroid Society (LATS), from whom data were collected exclusively by the world-wide web, to assess the diagnostic and therapeutic approaches concerning the nontoxic multinodular goiter. The results of this survey were compared with those from similar American Thyroid Association (ATA) and European Thyroid Association (ETA) surveys (1, 2).
Materials and Methods
Questionnaire
The LATS members living in Latin American countries were invited, by electronic messages (E-mail), to respond to an online questionnaire. Each participant received one personal password to enter the questionnaire homepage and could give only one response.
The electronic questionnaire was constructed by use of Macromedia Dreamweaver MX 7.0.1 (Macromedia, San Francisco, CA) and was stored in an online domain (www.lats.med.br) linked to a database. The first part of the questionnaire was composed of a hypothetical case report also used in the previous surveys (1, 2, 3). (A 42-yr-old premenopausal Caucasian woman is seen in your hospital/clinic due to an irregular, nontender, bilaterally enlarged thyroid, approximately 50–80 g. There is no lymphadenopathy. The goiter has been present for 3–5 yr and the patient reports moderate local neck discomfort. There are no symptoms of thyroid dysfunction or anterior neck pain, no family history of thyroid disease, and no previous external irradiation.) This was followed by questions related to the diagnostic investigations (in vitro and in vivo tests) and therapeutic preferences for the index case. In the second part, 11 variations of the index case were listed (Table 1), with only one variable changed for each variation, and the participants were asked to indicate for each variation whether the management plan was changed and, if so, the alterations in diagnostic and therapeutic procedures. Apart from the translation to Portuguese and the addition of new therapeutic options [i.e. recombinant human TSH (rhTSH) and percutaneous ethanol injection therapy (PEIT)], the questionnaire was similar to that previously employed (1, 2, 3).
Data analysis and statistical methods
Data obtained from the participants’ responses were stored in an electronic database of MS Access 11.0 (Microsoft Corp., Redmond, WA) and tabulated in an MS Excel 9.0 file (Microsoft). Statistical software used was Epi-Info 6.0.2 (CDC, Atlanta, GA). Results are predominantly given as percentages. The 2 test (or Fisher’s exact test) was used to test for differences between groups and to compare the results from the present study with those from the ATA and ETA surveys (1, 2). P < 0.05 was considered significant.
Results
Survey response and characteristics of respondents
In October 2003, 427 specialists living in Latin America were members of LATS. From these, a total of 304 E-mail addresses were obtained from the LATS directory. Electronic reminders were periodically sent to all of these members between November 2003 and April 2004. Seven members were excluded because they were not clinically active. From the 297 remaining members, we obtained 148 responses (response rate, 49.8%). Seventy-nine members did not receive the invitation because their electronic addresses were incorrect or did not exist. Fifty-six responses originated from teams of three to five clinicians working together.
More than half (58.8%) of the responses were from Brazilian clinicians; 22.3% were from Argentina, 6.7% from Chile, 3.4% from Paraguay, 3.4% from Colombia, 2% from Uruguay, 1.3% from Costa Rica, and the remaining from Bolivia, Ecuador, and Mexico (0.7% each). From the respondents, 76.3% were endocrinologists, 14.9% were surgeons, 4.0% were specialists in nuclear medicine, and the remainder had other specialties. Seventy-nine (53.4%) of the respondents had treated more than 50 patients with nontoxic multinodular goiter within the previous 6 months.
In vitro diagnostic procedures in the index case (Table 2)
The median number of blood tests used by the participants was five (range, 0–11). A serum TSH determination was the commonest biochemical test, used by 142 participants (95.9%), and it was the only blood test indicated by six (4%). At least one thyroid hormone assay (total and/or free T3 or T4) was included by 111 (75%), and among those, free T4 was the most frequently used. Investigation of thyroid autoantibodies was performed by 123 clinicians (83.1%), most often antithyroid peroxidase antibodies (TPO-Ab), which was used by 76.3%. Only eight respondents (5.4%) included serum calcitonin in the initial evaluation. Simultaneous use of serum TSH, a thyroid hormone assay (T3 and/or T4), and TPO-Ab was the most common combination, employed by 61.5%.
In vivo diagnostic procedures in the index case (Table 3)
Imaging of the thyroid gland, scintigraphy or ultrasound (US), was requested by 133 respondents (89.9%). US was clearly preferred to scintigraphy (89.9% vs. 16.2%), and the latter method was always used in combination with US. If US was ordered, morphology (gray scale) was applied by 90.2%, size determination by 81.9%, and Doppler by 58.4%. For scintigraphy, the isotopes of choice were 131I (75%), 99mTc (20.8%), and 123I (4.2%). Forty-one clinicians (27.7%) suggested an x-ray of the trachea/thorax, six of whom would additionally include an oral barium esophageal examination. Cervical computed tomography (CT) and magnetic resonance imaging (MRI) were requested by 18 (12.2%) and eight (5.4%) thyroidologists, respectively.
The vast majority (87.8%) of LATS members would use a fine needle aspiration biopsy (FNAB) in the index case, 74.6% of them with US guidance. All participants who requested scintigraphy also found indications for FNAB, independent of the scintigraphic characteristics of the thyroid.
Treatment in the index case (Table 4)
The LATS members far from agreed on the therapeutic recommendation in the index case. However, most recommended observation (39.2%), followed by surgery as the second choice (28.4%). The majority (81%) of those advocating no treatment would follow the patient in their own clinic or institution. Among respondents recommending surgery, 50% preferred near-total thyroidectomy, and 50% chose total thyroidectomy. Use of levothyroxine (L-T4) suppressive therapy postoperatively in a euthyroid patient to avoid goiter recurrence was advocated by 61.9%. L-T4 suppressive therapy as first-line therapy was recommended by 20.9% (details of L-T4 are given in Table 4). About two thirds of clinicians favoring L-T4 would advise a target level of serum TSH between 0.1–0.3 mU/liter and a duration of treatment of 6–24 months. Most (81%) used a fixed L-T4 dose. Radioiodine was the therapeutic choice of 10 respondents (6.7%), of whom six would use rhTSH (0.1 mg) stimulation before radioiodine.
Clinical variations: altered management (Table 5 and Fig. 1)
The most pronounced change in management was observed in clinical variations 1 (suppressed TSH; 74.3%) and 7 (rapid growth and very firm consistency; 70.3%). In addition, a significant shift in attitude was seen in the case of a large thyroid with major discomfort (64.9%), a prominent cystic nodule (56.7%), a history of external radiation of head/neck (55.4%), a family history of thyroid cancer (54.7%), and a patient aged 75 yr (52.7%; Fig. 1, right). Table 5 highlights the additional tests (not stated in the index case) that have been ordered by the participants for each clinical variation. Serum calcitonin was included in the diagnostic workup by an additional 23.6% of the respondents in the case of a family history of thyroid cancer. CT and/or MRI were added by 8.8% and 10.1%, respectively, in patients with a partly intrathoracic thyroid or a large gland with discomfort.
Figure 1 (left) shows changes in the therapeutic recommendation regarding the five major treatment options for each clinical variation. If TSH is suppressed, radioiodine becomes the therapy most frequently recommended (45.3%). This treatment is also an important option (recommended by 20.3%) in elderly patients. If there was concern about thyroid malignancy (variations 5–7) or pronounced discomfort due to thyroid growth (variations 8–9), surgery was preferred to other therapies, recommended by 52–78% of clinicians. A small thyroid, causing no discomfort, made 53.4% of the respondents suggest observation. For prominent cystic nodules, assessed by US, a high number of the clinicians advocated PEIT (33.8%) or only aspiration of the cyst (2%). A clinically significant shift in strategy, from an initially destructive therapy (surgery, radioiodine, or PEIT) to a more conservative strategy, or vice versa, was evident for eight clinical variations [no. 1, 6–9, and 11 (P < 0.001) and no. 4 and 5 (P < 0.05)].
Regional differences within Latin America
Comparisons were made among countries that participated with a minimum of 10 respondents: Brazil (n = 87), Argentina (n = 33) and Chile (n = 10). Scintigraphy was less commonly performed in Brazil (10.3%) than in Argentina (27.3%; P = 0.02), whereas US was used equally in all regions. In Argentina, more respondents included radiographic imaging such as x-ray or CT/MRI (60.6% vs. 42.5% in Brazil and 30% in Chile; not significantly different). L-T4 suppressive therapy was more commonly used in Argentina (42.4%) than in Brazil (12.6%; P < 0.001) and Chile (20%; not significantly different). Radioiodine therapy was used exclusively by Brazilian clinicians in the index case (11.5%). The surgical method of choice was total thyroidectomy in Brazil and near-total thyroidectomy in Chile, whereas in Argentina, each method had the same number of indications.
Comparison between surgeons and endocrinologists
We compared the management trends of endocrinologists (n = 113) with those of surgeons (n = 22). There were no major differences in the biochemical set-up for the index case between the two groups. Scintigraphy was used exclusively by endocrinologists, who also recommended FNAB more frequently (94.7% vs. 72.7%; P < 0.01). Thyroidectomy was chosen by 59% of surgeons and by 25.7% of endocrinologists (P < 0.01). Endocrinologists used L-T4 (23.9% vs. 4.5%; P = 0.02) and radioiodine (6.2% vs. 0%; not significantly different) more often than surgeons. A pronounced disagreement was found in the case of suppressed TSH levels; radioiodine therapy was preferred by 71.7% of endocrinologists and 9.1% of surgeons (P < 0.001).
Comparison with ATA and ETA surveys (Table 6)
Generally, LATS members follow a similar pattern as their ATA and ETA colleagues in their biochemical evaluations of the index case, although calcitonin (31.7%) and free T3 (43.3%) are used more often in Europe (P < 0.001; Table 2). ETA members perform more extensive imaging evaluation than ATA members: more than 80% use US and about three quarters request scintigraphy (both techniques in 70%) in Europe, whereas in North America clinicians order US in about 60% and scintigraphy in a quarter of cases (no imaging is the choice of 28.6%). LATS members order US as often as ETA members (90%), whereas thyroid scintigraphy is requested by as few as in North America (16%). In contrast, LATS members favor the use of radiographic examinations, including CT/MRI, in the evaluation of multinodular goiter. FNAB is extensively used by members of all three associations (Table 3).
Some disagreement exists among the three societies in the therapeutic preferences. L-T4 therapy is generally less used in Latin American than on the other two continents (P < 0.001; Table 6). Instead, LATS members seem more prone to taking a surgical approach, particularly in comparison with the ATA. L-T4 therapy was less used in Latin America in all variations (data not shown). For cystic nodules, percutaneous ethanol injection therapy is much more often used in Latin America and Europe (33–36%) than in North America (7.9%; P < 0.001). There were no significant differences in the management of variations 1, 4–6, and 9 among the three societies (data not shown).
Discussion
Our use of an electronic medium in this survey probably optimized the response rate, although it reached the same level (50%) as those of surveys previously performed in North America, Europe, and Australia (1, 2, 3). This online approach is relatively inexpensive and allows great agility and simplicity in the collection and analysis of data. To our knowledge, this is the first large-scale thyroid survey made with this methodology. We are aware of the fact that the management trends among physicians not affiliated with LATS, who treat the majority of patients with nontoxic multinodular goiter, may be different from those reported here. Nevertheless, this study summarizes the diagnostic and therapeutic approaches of a large group of thyroidologists; furthermore, it provides an opportunity for performing comparisons with similar ATA and ETA surveys (1, 2).
The laboratory evaluation in Latin America does not differ much from that performed on other continents. Guidelines recommend measurement of serum TSH in all cases of nodular goiter, whereas thyroid hormone assays add little additional information and should be reserved for cases with suppressed TSH (4, 5). Nevertheless, free T4 assessment is performed frequently by members of all associations (54–74%). Probably to disclose the coexistence of chronic autoimmune thyroiditis, ETA (1) and LATS members use evaluation of TPO-Ab more often than do ATA members (2), reflecting a more restrictive diagnostic work-up in North America.
Several studies (6, 7, 8), mostly of European origin, indicate that serum calcitonin measurement is more sensitive than FNAB for diagnosis of medullary thyroid cancer, although it is associated with a high false positive rate of 60–80% (9). A recent large-scale study indicated that routine use of serum calcitonin enables an earlier diagnosis of medullary thyroid cancer, leading to a better prognosis for this disease (8). LATS and ATA members include calcitonin measurement much less than Europeans (3–5% vs. 32%). The ATA (4) and the American Association of Clinical Endocrinologists (5) do not recommend routine use of serum calcitonin due to cost-benefit concerns, but this test is suggested in cases of a family history of thyroid cancer.
Guidelines (4, 5) that do not unequivocally recommend thyroid imaging in the initial evaluation of nodular goiter are not in line with the present attitudes of many thyroidologists, because US is routinely requested by 84% of ETA members (1) and by 90% of LATS members, significantly more often than by ATA members (60%) (2). The widespread use of US probably relies on its high sensitivity for detection of focal lesions, low cost, low risk, and its ability to provide guidance for FNAB (9). Neither US nor scintigraphy can accurately differentiate malignant from benign lesions, but scintigraphy may be useful for determining the functional status of thyroid nodules (4, 5, 9). Latin American and North American thyroidologists use scintigraphy (16% and 24%, respectively) to a much lesser extent than European experts (76%) (1, 2). The reasons for this discrepancy may well be tradition, a difference in the specialty composition of the responders, cost-benefit concerns in a managed care system of health such as that in North American, and the increasing use of nonsurgical therapy (radioiodine) in Europe. When using scintigraphy, each continent has a different radioisotope of choice: LATS members prefer 131I, whereas Europeans favor 99mTc (1). The North American physicians (2) act in accordance with American Association of Clinical Endocrinologists guidelines (5) that recommend 123I, which, although it is the most expensive isotope, results in the best thyroid scintiscans. Surprisingly, CT and MRI, both of which are expensive, were more often used by LATS members than by ATA and ETA members (1, 2). These techniques are not recommended for the initial evaluation, except in the case of substernal goiters with airway compression (9).
LATS and ETA (1) members order FNAB to a similar extent (88% and 93%), and more often than do ATA members (74%) (2). FNAB is considered to be the most reliable method to determine whether a thyroid nodule is malignant, especially in papillary tumors (4, 5, 9). The positive and negative predictive values may be improved if US is used for biopsy guidance (9).
Regarding therapeutic options, nearly 40% of LATS respondents preferred no treatment in the index case, slightly higher than reported in the ATA (2) and the ETA (1). In Australia, an even higher proportion of physicians (two of three) chose this strategy (3). LATS members use L-T4 as rarely as Australian respondents (3), in sharp contrast with its very frequent use within ATA and ETA (1, 2). This discrepancy may to some extent be explained by the time gap between these surveys, because the newest guidelines no longer recommend L-T4 use for nontoxic goiter. In fact, the most recent publications unanimously address the growing evidence of low efficacy of this therapy, with goiter regrowth after L-T4 discontinuation in the majority of cases, and the risks associated with long-term use of the drug, especially in elderly patients who are more susceptible to the deleterious effects of sustained subclinical hyperthyroidism (e.g. bone loss, atrial fibrillation, and neuropsychiatric and cognitive effects) (9, 10, 11, 12).
Surgical treatment proved to be the second principal option for the index case in Latin America, more frequently used than in Europe and North America (1, 2). Not surprisingly, surgery is more often recommended by surgeons (60%) than by clinical endocrinologists (26%). The major advantages of surgical therapy are rapid decompression of cervical structures and symptomatic relief as well as histopathological examination of the thyroid tissue. L-T4 after subtotal thyroidectomy to avoid goiter recurrence is generally not recommended due to its low efficacy (9, 13). However, a significant number of the LATS clinicians use L-T4 suppressive therapy in the euthyroid patient.
Few LATS clinicians recommend radioiodine in the index case, in agreement with previous surveys (1, 2, 3). No surgeon suggested radioiodine in the index case, as also was evident in the Australian survey (3). In many countries, radioiodine therapy for nontoxic goiter, resulting in a goiter reduction of 40–60%, still seems restricted to older patients with a high surgical risk. Prestimulation with rhTSH (recommended by six LATS members) has been shown to double the 24-h 131I uptake (14) in nontoxic multinodular goiter and allows the use of a smaller 131I dose, resulting in less extrathyroidal irradiation, apparently without impairing the effect on goiter size reduction (15). However, important safety issues still need to be clarified before rhTSH can be used routinely (16, 17). Cystic lesions may be responsible for 15–25% of solitary thyroid nodules, and most are benign (13, 18). LATS associates suggest PEIT in prominent cystic nodules as often as ETA respondents (1) (approximately one third of the respondents), whereas this method is rarely used within the ATA (2). The frequent use of this method is justified because ultrasound-guided PEIT in recurrent cysts results in a cure rate of 82% with a 6-month follow-up, compared with 48% after saline injection (19).
The clinical variations elicited additional investigations to a similar degree in Latin America as in the other surveys (1, 2, 3). An even higher ratio of LATS physicians recommend radioiodine when serum TSH is suppressed. In several of the other variations, LATS and ETA members generally prefer surgery more often than their ATA colleagues.
We conclude that no consensus exists regarding the ideal management of nontoxic multinodular goiter among LATS members, a disagreement previously also disclosed within the ATA and the ETA (1, 2). In Latin America, as in North America and Europe, serum TSH, US, and FNAB are the most important diagnostic tools. Compared with their ATA and ETA colleagues, LATS members use L-T4 suppression therapy much less, but are more prone to recommend surgery. On all three continents there is a very limited use of radioiodine. With regard to clinical variations, the Latin American and European attitudes are fairly comparable and are different from those prevailing in North America.
Acknowledgments
We thank all members of the LATS who contributed to the study by answering the questionnaire; Genzyme of Brazil for kindly sponsoring the study; Dr. Alexandre José Faria Carrilho, who stimulated us to initiate this work; Dr. Ana Carolina Gon?alves Ferreira for helping with manuscript preparing; and finally, Thiago Prado de Campos and Dhiego Augusto S. Bicudo for developing the electronic questionnaire and databases.
Footnotes
This work was supported in part by grants from Genzyme of Brazil. The results were presented in part at the 11th Brazilian Thyroid Meeting, Vitória, Brazil, June 10–13, 2004.
First Published Online October 13, 2004
Abbreviations: CT, Computed tomography; FNAB, fine needle aspiration biopsy; MRI, magnetic resonance imaging; PEIT, percutaneous ethanol injection therapy; rhTSH, recombinant human TSH; TPO-Ab, antithyroid peroxidase antibody; US, ultrasound.
Received August 28, 2004.
Accepted October 4, 2004.
References
Bonnema SJ, Bennedb?k FN, Wiersinga WM, Hegedüs L 2000 Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol (Oxf) 53:5–12
Bonnema SJ, Bennedb?k FN, Ladenson PW, Hegedüs L 2002 Management of the nontoxic multinodular goiter: a North American survey. J Clin Endocrinol Metab 87:112–117
Bhagat MC, Dhaliwal SS, Bonnema SJ, Hegedus L, Walsh JP 2003 Differences between endocrine surgeons and endocrinologists in the management of non-toxic multinodular goitre. Br J Surg 90:1103–1112
Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG 1996 Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 156:2165–2172
Feld S, Garcia M, Baskin HJ, Cobin RH, Gharib H, Hay ID, Kaplan MM, Mazzaferri EL et al. 1996 AACE clinical practice guidelines for the diagnosis and management of thyroid nodules. Endocr Pract 2:78–84
Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ, Yang JH, Chung JH 2001 Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid 11:73–80
Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A 1994 Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 78:826–829
Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F 2004 Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10.864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89:163–168
Hegedüs L, Bonnema SJ, Bennedb?k FN 2003 Management of simple nodular goiter: current status and future perspectives. Endocr Rev 24:102–132
Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY 1996 Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 81:4278–4289
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA 2001 Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 358:861–865
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ 2004 Subclinical thyroid disease: scientific review and guidelines for diagnosis and treatment. JAMA 291:228–238
Hegedüs L, Nygaard B, Hansen JM 1999 Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab 84:756–760
Huysmans DA, Nieuwlaat W, Erdtsieck J, Schellekens AP, Bus JW, Bravenboer B, Hermus AR 2000 Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodine uptake in nontoxic nodular goiter. J Clin Endocrinol Metab 85:3592–3596
Nieuwlaat WA, Huysmans DA, Van Den Bosch HC, Sweep CG, Ross HA, Corstens FH, Hermus AR 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:3121–3129
Bonnema SJ, Nielsen VE, Hegedus L 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:6113–6114
Nielsen VE, Bonnema SJ, Hegedus L 2004 Effects of 0.9 mg recombinant human thyrotropin on thyroid size and function in normal subjects: a randomized, double-blind, cross-over trial. J Clin Endocrinol Metab 89:2242–2247
Mazzaferri EL 1993 Management of a solitary thyroid nodule. N Engl J Med 328:553–559
Bennedbaek FN, Hegedüs L 2003 Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab 88:5773–5777(Leandro Arthur Diehl, Val)
To assess diagnostic and therapeutic approaches to nontoxic multinodular goiter and to compare them with previously reported American Thyroid Association (ATA) and European Thyroid Association (ETA) surveys, an online questionnaire was distributed to Latin American Thyroid Society (LATS) members. An index case was presented (42-yr-old woman with an enlarged, irregular, nontender, 50- to 80-g thyroid and no clinical suspicion of malignancy or dysfunction), and 11 variations were proposed to evaluate how each alteration would affect management. We obtained 148 responses (response rate, 50%). In the index case, the most used blood tests were TSH (96%), antithyroid peroxidase antibodies (76%), and free T4 (64%); 5% included a calcitonin assay. Nearly 90% would perform ultrasound, and only 16% used scintigraphy. Fine needle biopsy was indicated by 88%, with ultrasound guidance in 75% of times. For treatment, observation was preferred by 39%, surgery by 28%, levothyroxine by 21%, and radioiodine by 7% (60% with recombinant TSH prestimulation). A suppressed TSH level prompted 45% of the respondents to recommend radioiodine, whereas 70–78% indicated surgery in the presence of a large goiter or suspicion of malignancy. In conclusion, no consensus exists concerning the ideal management of nontoxic goiter among LATS members, in agreement with previous ATA and ETA surveys. Levothyroxine therapy is less used by LATS than by ATA or ETA members, and a more aggressive therapeutic strategy is generally preferred by members of LATS and ETA compared with ATA.
Introduction
NONTOXIC MULTINODULAR GOITER is one of the most prevalent thyroid disorders worldwide and sometimes impairs health and well-being. The optimum management of a patient with nontoxic goiter remains controversial, because well designed clinical studies to support the elaboration of guidelines are sparse or nonexistent. Previous studies have revealed trends in the management of nontoxic multinodular goiter in Europe (1), North America (2), and Australia (3), showing significant variations and regional preferences among thyroidologists. We conducted this survey among members of the Latin American Thyroid Society (LATS), from whom data were collected exclusively by the world-wide web, to assess the diagnostic and therapeutic approaches concerning the nontoxic multinodular goiter. The results of this survey were compared with those from similar American Thyroid Association (ATA) and European Thyroid Association (ETA) surveys (1, 2).
Materials and Methods
Questionnaire
The LATS members living in Latin American countries were invited, by electronic messages (E-mail), to respond to an online questionnaire. Each participant received one personal password to enter the questionnaire homepage and could give only one response.
The electronic questionnaire was constructed by use of Macromedia Dreamweaver MX 7.0.1 (Macromedia, San Francisco, CA) and was stored in an online domain (www.lats.med.br) linked to a database. The first part of the questionnaire was composed of a hypothetical case report also used in the previous surveys (1, 2, 3). (A 42-yr-old premenopausal Caucasian woman is seen in your hospital/clinic due to an irregular, nontender, bilaterally enlarged thyroid, approximately 50–80 g. There is no lymphadenopathy. The goiter has been present for 3–5 yr and the patient reports moderate local neck discomfort. There are no symptoms of thyroid dysfunction or anterior neck pain, no family history of thyroid disease, and no previous external irradiation.) This was followed by questions related to the diagnostic investigations (in vitro and in vivo tests) and therapeutic preferences for the index case. In the second part, 11 variations of the index case were listed (Table 1), with only one variable changed for each variation, and the participants were asked to indicate for each variation whether the management plan was changed and, if so, the alterations in diagnostic and therapeutic procedures. Apart from the translation to Portuguese and the addition of new therapeutic options [i.e. recombinant human TSH (rhTSH) and percutaneous ethanol injection therapy (PEIT)], the questionnaire was similar to that previously employed (1, 2, 3).
Data analysis and statistical methods
Data obtained from the participants’ responses were stored in an electronic database of MS Access 11.0 (Microsoft Corp., Redmond, WA) and tabulated in an MS Excel 9.0 file (Microsoft). Statistical software used was Epi-Info 6.0.2 (CDC, Atlanta, GA). Results are predominantly given as percentages. The 2 test (or Fisher’s exact test) was used to test for differences between groups and to compare the results from the present study with those from the ATA and ETA surveys (1, 2). P < 0.05 was considered significant.
Results
Survey response and characteristics of respondents
In October 2003, 427 specialists living in Latin America were members of LATS. From these, a total of 304 E-mail addresses were obtained from the LATS directory. Electronic reminders were periodically sent to all of these members between November 2003 and April 2004. Seven members were excluded because they were not clinically active. From the 297 remaining members, we obtained 148 responses (response rate, 49.8%). Seventy-nine members did not receive the invitation because their electronic addresses were incorrect or did not exist. Fifty-six responses originated from teams of three to five clinicians working together.
More than half (58.8%) of the responses were from Brazilian clinicians; 22.3% were from Argentina, 6.7% from Chile, 3.4% from Paraguay, 3.4% from Colombia, 2% from Uruguay, 1.3% from Costa Rica, and the remaining from Bolivia, Ecuador, and Mexico (0.7% each). From the respondents, 76.3% were endocrinologists, 14.9% were surgeons, 4.0% were specialists in nuclear medicine, and the remainder had other specialties. Seventy-nine (53.4%) of the respondents had treated more than 50 patients with nontoxic multinodular goiter within the previous 6 months.
In vitro diagnostic procedures in the index case (Table 2)
The median number of blood tests used by the participants was five (range, 0–11). A serum TSH determination was the commonest biochemical test, used by 142 participants (95.9%), and it was the only blood test indicated by six (4%). At least one thyroid hormone assay (total and/or free T3 or T4) was included by 111 (75%), and among those, free T4 was the most frequently used. Investigation of thyroid autoantibodies was performed by 123 clinicians (83.1%), most often antithyroid peroxidase antibodies (TPO-Ab), which was used by 76.3%. Only eight respondents (5.4%) included serum calcitonin in the initial evaluation. Simultaneous use of serum TSH, a thyroid hormone assay (T3 and/or T4), and TPO-Ab was the most common combination, employed by 61.5%.
In vivo diagnostic procedures in the index case (Table 3)
Imaging of the thyroid gland, scintigraphy or ultrasound (US), was requested by 133 respondents (89.9%). US was clearly preferred to scintigraphy (89.9% vs. 16.2%), and the latter method was always used in combination with US. If US was ordered, morphology (gray scale) was applied by 90.2%, size determination by 81.9%, and Doppler by 58.4%. For scintigraphy, the isotopes of choice were 131I (75%), 99mTc (20.8%), and 123I (4.2%). Forty-one clinicians (27.7%) suggested an x-ray of the trachea/thorax, six of whom would additionally include an oral barium esophageal examination. Cervical computed tomography (CT) and magnetic resonance imaging (MRI) were requested by 18 (12.2%) and eight (5.4%) thyroidologists, respectively.
The vast majority (87.8%) of LATS members would use a fine needle aspiration biopsy (FNAB) in the index case, 74.6% of them with US guidance. All participants who requested scintigraphy also found indications for FNAB, independent of the scintigraphic characteristics of the thyroid.
Treatment in the index case (Table 4)
The LATS members far from agreed on the therapeutic recommendation in the index case. However, most recommended observation (39.2%), followed by surgery as the second choice (28.4%). The majority (81%) of those advocating no treatment would follow the patient in their own clinic or institution. Among respondents recommending surgery, 50% preferred near-total thyroidectomy, and 50% chose total thyroidectomy. Use of levothyroxine (L-T4) suppressive therapy postoperatively in a euthyroid patient to avoid goiter recurrence was advocated by 61.9%. L-T4 suppressive therapy as first-line therapy was recommended by 20.9% (details of L-T4 are given in Table 4). About two thirds of clinicians favoring L-T4 would advise a target level of serum TSH between 0.1–0.3 mU/liter and a duration of treatment of 6–24 months. Most (81%) used a fixed L-T4 dose. Radioiodine was the therapeutic choice of 10 respondents (6.7%), of whom six would use rhTSH (0.1 mg) stimulation before radioiodine.
Clinical variations: altered management (Table 5 and Fig. 1)
The most pronounced change in management was observed in clinical variations 1 (suppressed TSH; 74.3%) and 7 (rapid growth and very firm consistency; 70.3%). In addition, a significant shift in attitude was seen in the case of a large thyroid with major discomfort (64.9%), a prominent cystic nodule (56.7%), a history of external radiation of head/neck (55.4%), a family history of thyroid cancer (54.7%), and a patient aged 75 yr (52.7%; Fig. 1, right). Table 5 highlights the additional tests (not stated in the index case) that have been ordered by the participants for each clinical variation. Serum calcitonin was included in the diagnostic workup by an additional 23.6% of the respondents in the case of a family history of thyroid cancer. CT and/or MRI were added by 8.8% and 10.1%, respectively, in patients with a partly intrathoracic thyroid or a large gland with discomfort.
Figure 1 (left) shows changes in the therapeutic recommendation regarding the five major treatment options for each clinical variation. If TSH is suppressed, radioiodine becomes the therapy most frequently recommended (45.3%). This treatment is also an important option (recommended by 20.3%) in elderly patients. If there was concern about thyroid malignancy (variations 5–7) or pronounced discomfort due to thyroid growth (variations 8–9), surgery was preferred to other therapies, recommended by 52–78% of clinicians. A small thyroid, causing no discomfort, made 53.4% of the respondents suggest observation. For prominent cystic nodules, assessed by US, a high number of the clinicians advocated PEIT (33.8%) or only aspiration of the cyst (2%). A clinically significant shift in strategy, from an initially destructive therapy (surgery, radioiodine, or PEIT) to a more conservative strategy, or vice versa, was evident for eight clinical variations [no. 1, 6–9, and 11 (P < 0.001) and no. 4 and 5 (P < 0.05)].
Regional differences within Latin America
Comparisons were made among countries that participated with a minimum of 10 respondents: Brazil (n = 87), Argentina (n = 33) and Chile (n = 10). Scintigraphy was less commonly performed in Brazil (10.3%) than in Argentina (27.3%; P = 0.02), whereas US was used equally in all regions. In Argentina, more respondents included radiographic imaging such as x-ray or CT/MRI (60.6% vs. 42.5% in Brazil and 30% in Chile; not significantly different). L-T4 suppressive therapy was more commonly used in Argentina (42.4%) than in Brazil (12.6%; P < 0.001) and Chile (20%; not significantly different). Radioiodine therapy was used exclusively by Brazilian clinicians in the index case (11.5%). The surgical method of choice was total thyroidectomy in Brazil and near-total thyroidectomy in Chile, whereas in Argentina, each method had the same number of indications.
Comparison between surgeons and endocrinologists
We compared the management trends of endocrinologists (n = 113) with those of surgeons (n = 22). There were no major differences in the biochemical set-up for the index case between the two groups. Scintigraphy was used exclusively by endocrinologists, who also recommended FNAB more frequently (94.7% vs. 72.7%; P < 0.01). Thyroidectomy was chosen by 59% of surgeons and by 25.7% of endocrinologists (P < 0.01). Endocrinologists used L-T4 (23.9% vs. 4.5%; P = 0.02) and radioiodine (6.2% vs. 0%; not significantly different) more often than surgeons. A pronounced disagreement was found in the case of suppressed TSH levels; radioiodine therapy was preferred by 71.7% of endocrinologists and 9.1% of surgeons (P < 0.001).
Comparison with ATA and ETA surveys (Table 6)
Generally, LATS members follow a similar pattern as their ATA and ETA colleagues in their biochemical evaluations of the index case, although calcitonin (31.7%) and free T3 (43.3%) are used more often in Europe (P < 0.001; Table 2). ETA members perform more extensive imaging evaluation than ATA members: more than 80% use US and about three quarters request scintigraphy (both techniques in 70%) in Europe, whereas in North America clinicians order US in about 60% and scintigraphy in a quarter of cases (no imaging is the choice of 28.6%). LATS members order US as often as ETA members (90%), whereas thyroid scintigraphy is requested by as few as in North America (16%). In contrast, LATS members favor the use of radiographic examinations, including CT/MRI, in the evaluation of multinodular goiter. FNAB is extensively used by members of all three associations (Table 3).
Some disagreement exists among the three societies in the therapeutic preferences. L-T4 therapy is generally less used in Latin American than on the other two continents (P < 0.001; Table 6). Instead, LATS members seem more prone to taking a surgical approach, particularly in comparison with the ATA. L-T4 therapy was less used in Latin America in all variations (data not shown). For cystic nodules, percutaneous ethanol injection therapy is much more often used in Latin America and Europe (33–36%) than in North America (7.9%; P < 0.001). There were no significant differences in the management of variations 1, 4–6, and 9 among the three societies (data not shown).
Discussion
Our use of an electronic medium in this survey probably optimized the response rate, although it reached the same level (50%) as those of surveys previously performed in North America, Europe, and Australia (1, 2, 3). This online approach is relatively inexpensive and allows great agility and simplicity in the collection and analysis of data. To our knowledge, this is the first large-scale thyroid survey made with this methodology. We are aware of the fact that the management trends among physicians not affiliated with LATS, who treat the majority of patients with nontoxic multinodular goiter, may be different from those reported here. Nevertheless, this study summarizes the diagnostic and therapeutic approaches of a large group of thyroidologists; furthermore, it provides an opportunity for performing comparisons with similar ATA and ETA surveys (1, 2).
The laboratory evaluation in Latin America does not differ much from that performed on other continents. Guidelines recommend measurement of serum TSH in all cases of nodular goiter, whereas thyroid hormone assays add little additional information and should be reserved for cases with suppressed TSH (4, 5). Nevertheless, free T4 assessment is performed frequently by members of all associations (54–74%). Probably to disclose the coexistence of chronic autoimmune thyroiditis, ETA (1) and LATS members use evaluation of TPO-Ab more often than do ATA members (2), reflecting a more restrictive diagnostic work-up in North America.
Several studies (6, 7, 8), mostly of European origin, indicate that serum calcitonin measurement is more sensitive than FNAB for diagnosis of medullary thyroid cancer, although it is associated with a high false positive rate of 60–80% (9). A recent large-scale study indicated that routine use of serum calcitonin enables an earlier diagnosis of medullary thyroid cancer, leading to a better prognosis for this disease (8). LATS and ATA members include calcitonin measurement much less than Europeans (3–5% vs. 32%). The ATA (4) and the American Association of Clinical Endocrinologists (5) do not recommend routine use of serum calcitonin due to cost-benefit concerns, but this test is suggested in cases of a family history of thyroid cancer.
Guidelines (4, 5) that do not unequivocally recommend thyroid imaging in the initial evaluation of nodular goiter are not in line with the present attitudes of many thyroidologists, because US is routinely requested by 84% of ETA members (1) and by 90% of LATS members, significantly more often than by ATA members (60%) (2). The widespread use of US probably relies on its high sensitivity for detection of focal lesions, low cost, low risk, and its ability to provide guidance for FNAB (9). Neither US nor scintigraphy can accurately differentiate malignant from benign lesions, but scintigraphy may be useful for determining the functional status of thyroid nodules (4, 5, 9). Latin American and North American thyroidologists use scintigraphy (16% and 24%, respectively) to a much lesser extent than European experts (76%) (1, 2). The reasons for this discrepancy may well be tradition, a difference in the specialty composition of the responders, cost-benefit concerns in a managed care system of health such as that in North American, and the increasing use of nonsurgical therapy (radioiodine) in Europe. When using scintigraphy, each continent has a different radioisotope of choice: LATS members prefer 131I, whereas Europeans favor 99mTc (1). The North American physicians (2) act in accordance with American Association of Clinical Endocrinologists guidelines (5) that recommend 123I, which, although it is the most expensive isotope, results in the best thyroid scintiscans. Surprisingly, CT and MRI, both of which are expensive, were more often used by LATS members than by ATA and ETA members (1, 2). These techniques are not recommended for the initial evaluation, except in the case of substernal goiters with airway compression (9).
LATS and ETA (1) members order FNAB to a similar extent (88% and 93%), and more often than do ATA members (74%) (2). FNAB is considered to be the most reliable method to determine whether a thyroid nodule is malignant, especially in papillary tumors (4, 5, 9). The positive and negative predictive values may be improved if US is used for biopsy guidance (9).
Regarding therapeutic options, nearly 40% of LATS respondents preferred no treatment in the index case, slightly higher than reported in the ATA (2) and the ETA (1). In Australia, an even higher proportion of physicians (two of three) chose this strategy (3). LATS members use L-T4 as rarely as Australian respondents (3), in sharp contrast with its very frequent use within ATA and ETA (1, 2). This discrepancy may to some extent be explained by the time gap between these surveys, because the newest guidelines no longer recommend L-T4 use for nontoxic goiter. In fact, the most recent publications unanimously address the growing evidence of low efficacy of this therapy, with goiter regrowth after L-T4 discontinuation in the majority of cases, and the risks associated with long-term use of the drug, especially in elderly patients who are more susceptible to the deleterious effects of sustained subclinical hyperthyroidism (e.g. bone loss, atrial fibrillation, and neuropsychiatric and cognitive effects) (9, 10, 11, 12).
Surgical treatment proved to be the second principal option for the index case in Latin America, more frequently used than in Europe and North America (1, 2). Not surprisingly, surgery is more often recommended by surgeons (60%) than by clinical endocrinologists (26%). The major advantages of surgical therapy are rapid decompression of cervical structures and symptomatic relief as well as histopathological examination of the thyroid tissue. L-T4 after subtotal thyroidectomy to avoid goiter recurrence is generally not recommended due to its low efficacy (9, 13). However, a significant number of the LATS clinicians use L-T4 suppressive therapy in the euthyroid patient.
Few LATS clinicians recommend radioiodine in the index case, in agreement with previous surveys (1, 2, 3). No surgeon suggested radioiodine in the index case, as also was evident in the Australian survey (3). In many countries, radioiodine therapy for nontoxic goiter, resulting in a goiter reduction of 40–60%, still seems restricted to older patients with a high surgical risk. Prestimulation with rhTSH (recommended by six LATS members) has been shown to double the 24-h 131I uptake (14) in nontoxic multinodular goiter and allows the use of a smaller 131I dose, resulting in less extrathyroidal irradiation, apparently without impairing the effect on goiter size reduction (15). However, important safety issues still need to be clarified before rhTSH can be used routinely (16, 17). Cystic lesions may be responsible for 15–25% of solitary thyroid nodules, and most are benign (13, 18). LATS associates suggest PEIT in prominent cystic nodules as often as ETA respondents (1) (approximately one third of the respondents), whereas this method is rarely used within the ATA (2). The frequent use of this method is justified because ultrasound-guided PEIT in recurrent cysts results in a cure rate of 82% with a 6-month follow-up, compared with 48% after saline injection (19).
The clinical variations elicited additional investigations to a similar degree in Latin America as in the other surveys (1, 2, 3). An even higher ratio of LATS physicians recommend radioiodine when serum TSH is suppressed. In several of the other variations, LATS and ETA members generally prefer surgery more often than their ATA colleagues.
We conclude that no consensus exists regarding the ideal management of nontoxic multinodular goiter among LATS members, a disagreement previously also disclosed within the ATA and the ETA (1, 2). In Latin America, as in North America and Europe, serum TSH, US, and FNAB are the most important diagnostic tools. Compared with their ATA and ETA colleagues, LATS members use L-T4 suppression therapy much less, but are more prone to recommend surgery. On all three continents there is a very limited use of radioiodine. With regard to clinical variations, the Latin American and European attitudes are fairly comparable and are different from those prevailing in North America.
Acknowledgments
We thank all members of the LATS who contributed to the study by answering the questionnaire; Genzyme of Brazil for kindly sponsoring the study; Dr. Alexandre José Faria Carrilho, who stimulated us to initiate this work; Dr. Ana Carolina Gon?alves Ferreira for helping with manuscript preparing; and finally, Thiago Prado de Campos and Dhiego Augusto S. Bicudo for developing the electronic questionnaire and databases.
Footnotes
This work was supported in part by grants from Genzyme of Brazil. The results were presented in part at the 11th Brazilian Thyroid Meeting, Vitória, Brazil, June 10–13, 2004.
First Published Online October 13, 2004
Abbreviations: CT, Computed tomography; FNAB, fine needle aspiration biopsy; MRI, magnetic resonance imaging; PEIT, percutaneous ethanol injection therapy; rhTSH, recombinant human TSH; TPO-Ab, antithyroid peroxidase antibody; US, ultrasound.
Received August 28, 2004.
Accepted October 4, 2004.
References
Bonnema SJ, Bennedb?k FN, Wiersinga WM, Hegedüs L 2000 Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol (Oxf) 53:5–12
Bonnema SJ, Bennedb?k FN, Ladenson PW, Hegedüs L 2002 Management of the nontoxic multinodular goiter: a North American survey. J Clin Endocrinol Metab 87:112–117
Bhagat MC, Dhaliwal SS, Bonnema SJ, Hegedus L, Walsh JP 2003 Differences between endocrine surgeons and endocrinologists in the management of non-toxic multinodular goitre. Br J Surg 90:1103–1112
Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG 1996 Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 156:2165–2172
Feld S, Garcia M, Baskin HJ, Cobin RH, Gharib H, Hay ID, Kaplan MM, Mazzaferri EL et al. 1996 AACE clinical practice guidelines for the diagnosis and management of thyroid nodules. Endocr Pract 2:78–84
Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ, Yang JH, Chung JH 2001 Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid 11:73–80
Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A 1994 Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 78:826–829
Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F 2004 Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10.864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89:163–168
Hegedüs L, Bonnema SJ, Bennedb?k FN 2003 Management of simple nodular goiter: current status and future perspectives. Endocr Rev 24:102–132
Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY 1996 Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 81:4278–4289
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA 2001 Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 358:861–865
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ 2004 Subclinical thyroid disease: scientific review and guidelines for diagnosis and treatment. JAMA 291:228–238
Hegedüs L, Nygaard B, Hansen JM 1999 Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab 84:756–760
Huysmans DA, Nieuwlaat W, Erdtsieck J, Schellekens AP, Bus JW, Bravenboer B, Hermus AR 2000 Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodine uptake in nontoxic nodular goiter. J Clin Endocrinol Metab 85:3592–3596
Nieuwlaat WA, Huysmans DA, Van Den Bosch HC, Sweep CG, Ross HA, Corstens FH, Hermus AR 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:3121–3129
Bonnema SJ, Nielsen VE, Hegedus L 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:6113–6114
Nielsen VE, Bonnema SJ, Hegedus L 2004 Effects of 0.9 mg recombinant human thyrotropin on thyroid size and function in normal subjects: a randomized, double-blind, cross-over trial. J Clin Endocrinol Metab 89:2242–2247
Mazzaferri EL 1993 Management of a solitary thyroid nodule. N Engl J Med 328:553–559
Bennedbaek FN, Hegedüs L 2003 Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab 88:5773–5777(Leandro Arthur Diehl, Val)