On the usefulness of levothyroxine suppressive therapy in the medical treatment of benign solitary, solid or predominantly solid, thyroid nodules Marco F. Divisione di Medicina1,

Celani, Maurizio Mariani and Giuliano Mariani

Ospedale di Castelfranco Emilia, Castelfranco Emilia, Modena, and Servizio di Endocrinología Ospedale dell'Aquila, L'Aquila, Italy

Abstract.

The efficacy of levothyroxine suppressive in the treatment of benign solitary thyroid nodules is controversial. In order to investigate this issue further we studied 122 patients with a solitary, solid or predominantly solid, thyroid nodule. The benign (colloid) nature of all nodules was proved by fine-needle aspiration biopsy. At the pertechnetate-99m thyroid scanning 91% of the nodules were "cold" and 9% "warm". All the patients received suppressive oral doses of levothyroxine (0.1 to 0.2 mg/day). Fifty-three patients were treated with levothyroxine for 6 months, 31 for 9 months and 38 for 12 months. The size of each nodule before and after treatment was evaluated by high-resolution ultrasonography. The actual suppression of TSH secretion was monitored at 3-month intervals using an ultrasensitive immunometric assay. At the end of levothyroxine treatment, patients were classified as responders (decrease in nodule volume \m=ge\50%,68/122 55.7%; mean percent change in nodule volume \m=-\77.1\m=+-\15.7%), partially responders 19.7%; (decrease in nodule volume 3 cm in 25. All the patients were clinically euthyroid, with normal levels of free T4 (FT4) (8.3 to 17.9 pmol/1, mean ±sd 13.4±3.0), free T3 (FT3) (3.7 to 8.4 pmol/1, mean ± sd 6.3±1.5), and TSH (0.4 to 3.8 mIU/1, mean ±sd 1.4±0.6). None of them had serious cardiovascular dis¬ ease and none of the female patients was pregnant. More¬ over, none of the patients was treated with thyroid hor¬ mone suppression before the present study or was on therapy known to affect thyroid or pituitary function. Finally, a history of neck irradiation was excluded in all tween

July

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subjects. Patients were treated with a single daily oral dose of L-T4 (given between 08.00 and 09.00 h) known to be suppressive, i.e. 2.2 pg per kg body weight (10,11). The daily suppressive dose of L-T4 (Eutirox, Braceo, Milan, Italy) ranged from 0.1 to 0.2 mg (mean±sD 1.4±0.4). The starting daily dose was 0.025 or 0.050 mg, which was =

increased stepwise, in increments of 0.025 or 0.050 mg every week, depending on the age and the cardiovascular status of the patients. The duration of L-T4 therapy was calculated from the beginning of the treatment with the suppressive dose. To confirm compliance with the suppressive therapy during the study, TSH levels were determined in each patient at 3-month intervals. At the end of the present study (March 1990), 56 pa¬ tients had been treated with suppressive doses of L-T4 for 6 months, 34 for 9 months, and 39 for 12 months. Nine¬ teen patients were excluded because of non-suppressed TSH levels, 9 at the end of the 3rd month of L-T4 ther¬ apy, 5 at the end of the 6th month, 2 at the end of the 9th month, and 3 at the end of the 12th month, respectively. Each of the excluded patients admitted a lack of complicance with L-T4 therapy. Therefore, the final study pop¬ ulation consisted of 122 patients with persistently suppressed TSH levels (118 females and 4 males, mean age ±sd 44.4± 12.9). Eighty-seven of their solitary nod¬ ules were solid, 35 predominantly solid, 111 "cold", 11 "warm", 68 were located in the right thyroid lobe, 39 in the left lobe and 15 in the isthmus. The maximal diameter was =S3 cm in 99 nodules and >3 cm in 23. Fifty-three patients (mean age ±sd 43.8± 12.3 years) had been treated with suppressive doses of L-T4 for 6 months, 31 (mean age +sd 45.5± 12.3 years) for 9 months, and 38 =

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(mean age ±sd 44.2± 14.3 years) for 12 months. In each of these 3 groups, the heart rate, the mean blood pressure ((systolic diastolic)/3 + diastolic), the body mass index (weight/square of the height), the nodule size (maximal diameter and volume) and the basal levels of FT4, FT3 and TSH were evaluated before the beginning of L-T4 suppression and after 6, 9 and 12 months, respectively. No intermediate measurements of the nodule size by ultrasonography were made. Venous blood samples for hormone evaluation were taken between 08.00 and 09.00 h. after an overnight fast. Serum FT4 and FT3 were assayed using commercial RIA kits (12). Normal values were: FT4 8-21 pmol/1, FT3 3.6-8.6 pmol/1. Serum TSH (normal range 0.3-5.0 mIU/1) was measured by an ultrasensitive immunoradiometric (IRMA) assay (10) (sensitivity 0.07 mIU/1). TSH secre¬ tion was considered suppressed when basal serum TSH was undetectable. Fine-needle aspiration biopsy (FNAB) was performed using a 25-gauge needle attached to a disposable 10-ml plastic syringe, according to the technique described by Hamburger et al. (13). In all patients the reference ultra¬ sound examination was carried out 30 to 60 days after FNAB, and L-T4 therapy was started 7 to 15 days after FNAB. If a second FNAB was performed, this was done after the ultrasonography at the completion of the study. Paired Student's t-test, analysis of variance (two-way ANOVA and Duncan's multiple comparison test), chisquare test, and linear regression analysis, when appro¬ priate, were employed for statistical evaluation; p-values less than 0.05 were considered to be significant. =

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Results On the basis of the nodule volume recorded at the end of L-T4 therapy, the 122 patients were classi¬ fied as responders (decrease in nodule volume 5=50%), partially responders (decrease in nodule volume 0.05) in the 3 groups. The pretreatment hormone levels were also similar (p>0.05). In each group, L-T4 therapy induced a significant rise in basal FT4 (p0.05). The FT4 concentrations were at the upper normal limit in 7 patients and in the normal range in 115 patients. None of the patients developed symptoms or signs of hyperthyroidism.

Table 1. Classification of 122

patients with a colloid solitary, (L-T4) suppression therapy (mean values ± sd).

Respondersa> N(%) Age (years)

24/122 (19.7) 42.7±14.2

16/122 (13.1)

43.9±12.7

45.4±9.0

14/122 (11.5) 48.4±15.3

8.4±2.6

9.0±2.5

8.4±2.5

9.4±2.8

1.4+0.3

1.4±0.3

1.3+0.2

1.4±0.3

2.3±0.9

2.6±1.0

1.7+1.2

2.3+1.4

2.3±0.9d)

1.7+1.2

(55.7)

1.3±0.7d) -42.9±17.8

Nodule volume (ml) Before therapy After therapy

change FT4 (pmol/1) Before therapy After therapy FT3 (pmol/1) Before therapy After therapy

2.8±1.5d) + 24.1 + 21.1

-10.3±4.3

4.8±5.5

2.6±5.6

0.9±1.7d>

3.5±4.2d>

2.6±5.6

-77.1 + 15.7

-27.5±10.1

3.3±4.0

%

Nonresponders

Partially

Increase in nodule volume

Mean duration of

change

predominantly solid, thyroid nodule after levothyroxine

No change in nodule volume

therapy (months) Mean daily dose of L-T4 (mg)

%

or

respondersb>

68/122

Maximal diameter of the nodule (cm) Before therapy After therapy

solid

5.1 ±8.4

7.8±11.9C) + 113.6+130.9

13.3±3.0

14.3±2.9

13.1+2.7

13.1+2.8

17.0±2.6d)

17.9±2.6d)

16.5±2.4d)

17.1±2.2d)

6.2±1.5 6.3±1.5

6.2±1.4

6.5+1.3

6.7±1.3 6.6±1.3

6.0±1.7 5.9±1.5

1.410.5

1.3±0.6

1.5±0.6

1.6±0.6

0.07d)

0.07d)

0.07d)

0.07d)

TSH (mIU/1) Before therapy After therapy

a) reduction of nodule volume 2=50%; b) reduction in nodule volume 3 cm (Table 3). In agreement with these findings, no significant relationships were shown in the responders between the percent change in nodule volume and the duration of L-T4 treatment (r 0.009, p>0.05) or the nodule volume before =

L-T4 therapy (r A similar

=

0.177, p>0.05).

proportion

of

responders (59.0%,

51.2% and 57.5%, when

respectively) was also found patients were divided into 3 age groups: 50 years (N=40), respectively. In the responder group no years

significant

correlation was observed between the decrease in nodule volume and the age of percent the patients (r=0.142, p>0.05). Finally, the proportion of responders was not sig¬ nificantly different (p>0.05) among patients with nodules located in the right lobe (51.5%), in the left lobe (59.0%) or in the isthmus (66.7%), nor be¬ tween patients with solid (58.6%) and predomi¬ nantly solid (48.6%) nodules. In 11 patients (9.0%) new nodules (1 to 3) were found by ultrasonography after L-T4 therapy. The proportion of patients with new nodules was higher, although not significantly (p>0.05), in the

Table 2.

Proportion of responders, partially responders and nonresponders, and changes in nodule volume in the three groups of patients treated with levothyroxine (L-T4) for 6, 9 or 12 months, respectively.

Nonresponders Duration of

L-T4

Responders

therapy

Partially responders

Six months N (%)

33/53(62.3)

8/53(15.1)

change

-77.1 +13.9

-25.8+10.5

in nodule volume Nine months N (%) % change in nodule volume Twelve months N (%) % change in nodule volume

%

16/31(51.6)

8/31(25.8)

-77.7±15.5

-25.3+10.0

19/38(50.0)

8/38(21.1)

-76.6±19.3

-26.9+4.0

nonresponder (4/30, 13.3%) than in the partially responder (3/24, 12.5%) and responder (4/68, 5.9%) groups, and in the patients treated with L-T4 for 12 months (6/38, 15.8%) compared with those

treated for 9(1/31, 3.2%) or 6 months (4/53, 7.5%). Twelve out of the nonresponders showing an in¬ crease in nodule volume in spite of L-T4 therapy underwent surgical excision of the nodule. In all cases the diagnosis of colloid goitre was confirmed. As far as the outcome of the 10 patients with non-suppressed TSH levels (in which ultrasonographic evaluation of the nodule size was per¬ formed) is concerned, an increase in nodule volume (by 12 to 38%) was found in 9 patients (90.0%, 4/5 at the 6th month, 2/2 at the 9th month,

No change in nodule volume

7/53(13.2)

Increase in nodule volume

5/53(9.4) +64.6±67.3

5/31(16.1)

2/31(6.5) +32.5±10.6

4/38(10.5)

7/38(18.4) +171.8+161.1

and 3/3 at the 12th month, respectively), whereas the nodule volume remained unchanged in one

patient (10.0%).

Discussion The usefulness of L-T4 therapy in the treatment of benign thyroid nodules has been criticized by Gharib et al. (6). They studied 53 patients with col¬ loid nodules (26 with a solitary nodule and 17 with 2 to 6 nodules). Twenty-eight patients were treated with L-T4 for 6 months and 25 with placebo. At the end of the 6-month trial, a significant decrease in nodule volume (=£50%) was observed in a similar

Table 3.

Proportion of responders, partially responders and nonresponders, and nodules with a maximal diameter =£3 cm or >3 cm.

Responders Nodule diameter =£3

Nonresponders No change in nodule volume

Increase in nodule volume

cm

N(%) %

Partially responders

changes in nodule volume in patients having

change in nodule volume

Nodule diameter >3 cm N (%) % change in nodule volume

55/99(56.6)

18/99(18.2)

-77.6±15.6

-29.2±10.3

12/23(52.2)

6/23(26.1)

-74.8±16.6

-22.4±7.8

14/99(14.1)

11/99(11.1) +135.5±140.6

2/23(8.7)

3/23(13.1) +33.3+15.6

proportion of L-T4-treated (4/28, 14.3%) and pla¬ cebo-treated (5/20, 20.0%) patients, despite the effective suppression of TSH secretion demon¬ strated in the former group. This finding was ascribed to a spontaneous reduction of the nodule volume in the placebo group. The authors con¬ cluded that "the efficacy of levothyroxine therapy in reducing the size of colloid thyroid nodules is not apparent within six months" and that the length of the trial of L-T4 therapy should be extended to a minimum of 12 months. More recently, Morita et al. (14) found a proportion of responders (reduc¬ tion in nodule volume >50%) as high as 36.7% in 49 patients with solitary benign thyroid nodules treated with L-T4 for 3 months. A similar propor¬ tion (42.3%) of responders (decrease in nodule volume ^50%) has been found by us in 18 patients treated with L-T4 for 4 months (data not shown). Moreover, in our present study no significant dif¬ ferences in the proportion of responders were ob¬ served in the three groups of patients treated with L-T4 for 6, 9 or 12 months. We can therefore suppose a nearly fixed threshold of responders after 6 months of L-T4 suppression. A decrease in nodule volume 5==50% was found by us in 56% of patients treated with suppressive doses of L-T4. Our data are consistent with the results of previous trials (4,15,16). These trials, however, have been criticized because of the failure to document the actual suppression of TSH secre¬ tion, the inadequate measurement of the nodule size and/or the imprecise histological definition of the nodule (3,6,17). To avoid these criticisms, the adequacy of TSH inhibition was confirmed in the present study by serum ultrasensitive TSH levels suppressed to undetectable values, the nodule size was measured by high-resolution ultrasound imag¬ ing and the colloid nature of each nodule was con¬ firmed by fine-needle aspiration biopsy. Moreover, because of the possibility that solitary and multiple thyroid nodules may have a different behaviour during L-T4 suppression (11,17), only the nodules proved to be solitary by high-resolution ultrasonography were examined. Cystic nodules were also excluded since their size is influenced by the needle aspiration of the cystic fluid. Compliance with L-T4 therapy during the study was confirmed by assess¬ ing TSH levels at 3-month intervals (18). Finally, erroneous inferences of fine-needle aspiration biopsy on the nodule volume (19) were avoided. A criticism on our investigation is the lack of a placebo group. On the other hand, it is unlikely that the

high proportion of responders patients and the re¬

markable mean percent decrease in nodule volume (77%) shown in our study were merely due to the spontaneous regression of the nodules. In addi¬ tion, the nodule volume was increased in most pa¬ tients excluded because of non-suppressed TSH levels. It is conceivable that differences in the nodule sensitivity to TSH, and therefore to TSH suppression, may exist in different geographic areas, e.g. in the USA (6), in Japan (14), and in Italy. Possibly variations in iodine intake could ex¬ plain some of the differences observed. We have also shown a decrease in volume lower than 50% in 20% of the solitary nodules and no changes in volume in 13%. Since the goal of L-T4 suppression is not the shrinkage of the nodules, but the prevention of further nodule growth (20,21), L-T4 therapy was effective in 88% of our patients. This result was with considering the initial volume of the nodules. L-T4 therapy was in fact effective in 87% of the nodules larger than 3 cm, which are considered to be less responsive to thyroid hor¬ mone

suppression (21). growth of some

nodules (12%) and the of nodules in some (9%) of our new appearance related could be an to incomplete suppres¬ patients sion of TSH secretion in spite of the undetectable basal TSH levels (10,22). Alternatively, the depen¬ dence of the nodule growth on growth factors other than TSH (14), and/or the natural heteroge¬ neity of thyroid follicles (23) could be responsible for these findings. In conclusion, L-T4 suppression appears to be a useful tool in the treatment of benign solitary, solid or predominantly solid, thyroid nodules. It is also a safe therapy, since the vital parameters (e.g. heart rate and blood pressure) are unaffected by 6 to 12 months treatment. Thus, in agreement with Griffin (3), a six-month test period of suppressive therapy should be tried in all patients with a solitary thyroid nodule proved to be colloid by fine-needle aspira¬ tion biopsy. The

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Metab 1987;64:849-55. 11. Mazzaferri EL, de los Santos ET, Rofagha-Keyhani S. Solitary thyroid nodule: diagnosis and ménagement. Med Clin North Am 1988;72:1177-211. 12. Celani MF, Giambuzzi G, Simoni M, Montanini V. Subnormal prolactin responsiveness to thyrotropinreleasing hormone (TRH) in women with primary empty sella syndrome. J Endocrinol Invest 1987; 10:421-5. 13. Hamburger JI, Miller JM, Kini SR. Diagnosis of thy¬ roid nodules by needle biopsy. In: Ingbar SH, Bra¬ verman LE, eds. Werner's the thyroid. 5th English

Gharib H. Nodular thyroid disease. Evaluation and ménagement. N Engl J Med 1985; 313:428-36. Wexler CB, Pepper GM, Bitton RN, Schneider BS. Letter. N EnglJ Med 1987;317:1663-4. HamburgerJI. Letter. N EnglJ Med 1987;317:1664. Watts NB. Letter. N EnglJ Med 1987;317:1663. Sisson JC. Medical treatment of benign and malig¬ nant thyroid tumors. Endocrinol Metab Clin North

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Received

May 10th, 1990.

Accepted August 14th,

1990.

Dr Marco F. Celani, Divisione di Medicina, Ospedale di Castelfranco Emilia, 1-41013 Castelfranco Emilia,

Modena,

Italy.

On the usefulness of levothyroxine suppressive therapy in the medical treatment of benign solitary, solid or predominantly solid, thyroid nodules.

The efficacy of levothyroxine suppressive therapy in the treatment of benign solitary thyroid nodules is controversial. In order to investigate this i...
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