help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brenta, G.
Right arrow Articles by Pisarev, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brenta, G.
Right arrow Articles by Pisarev, M. A.
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5287-5292
Copyright © 2003 by The Endocrine Society

Comparative Efficacy and Side Effects of the Treatment of Euthyroid Goiter with Levo-Thyroxine or Triiodothyroacetic Acid

G. Brenta, M. Schnitman, O. Fretes, E. Facco, M. Gurfinkel, S. Damilano, N. Pacenza, A. Blanco, E. Gonzalez and M. A. Pisarev

Department of Endocrinology and Metabolism (G.B., M.S., O.F., E.F., M.G., S.D., N.P., A.B., M.A.P.), French Hospital; Laboratory of Molecular Diagnosis-Biosidus; and Department of Radiobiology (E.G.), National Atomic Energy Commission and Department of Biochemistry (M.A.P.), University of Buenos Aires School of Medicine, Buenos Aires 1429, Argentina

Address all correspondence and requests for reprints to: Mario A. Pisarev, Department of Radiobiology, Comisión Nacional de Energía Atómica, Av del Libertador 8250, Buenos Aires 1429, Argentina. E-mail: pisarev{at}cnea.gov.ar.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Euthyroid goiter is usually treated with TSH-inhibitory doses of levo-T4 (L-T4). Because triiodothyroacetic acid (TRIAC) decreases TSH levels, the following study was perfomed: 36 euthyroid goitrous female patients (no cancer or chronic thyroiditis) were randomized to TRIAC (19.6 µg/kg) (n = 19) or L-T4 (1.7 µg/kg) (n = 17) treatment during 11 months. Goiter volume; lumbar and femoral bone mineral density; serum osteocalcin; deoxypyridinoline; TSH; free T4; total, high-density lipoprotein, and low-density lipoprotein cholesterol; and triglycerides were measured before and after the study period. Student’s t test and {chi}2 analysis were performed. TSH values (microunits per milliliter) in the TRIAC and L-T4 groups were: 1.91 ± 0.6 (basal) and 0.180 ± 0.1 (after) and 2.1 ± 2.5 (basal) and 0.180 ± 0.3 (after), respectively. Thyroid volume decreased 37.9 ± 35.4% in the TRIAC patients and 14.5 ± 39.5% in the L-T4 group (P = 0.069). Forty-two percent of the goiters with TRIAC reduced more than 50% their initial volume vs. 17.7% with L-T4 (P = 0.15). With TRIAC, patients experienced fewer side effects. No differences in the changes of bone mineral density, serum deoxypyridinoline, osteocalcin, or the lipid profile were observed between both groups. The present results show that TRIAC is more effective than L-T4 in the reduction of goiter size, with comparable effects on peripheral parameters.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
EUTHYROID GOITER IS usually treated with suppressive doses of thyroid hormone, mainly L-T4. This is based on the assumption that TSH plays a role in the development and/or progression of this pathology and that the inhibition of pituitary TSH could cause a regression of goiter or at least prevent its further growth. The results of this treatment have been quite variable, with decreases in goiter volume that spanned from negligible to complete disappearance (1, 2, 3, 4, 5). The early studies have been performed by evaluation of goiter size by palpation, which is unreliable and prone to subjective bias. In recent years the clinical studies were performed by thyroid sonography, which allows a more objective assessment of goiter volume. Although the results obtained by treating these patients with L-T4 have been acceptable, they are not devoid of undesired effects. Chronic administration of suppressive doses of L-T4 have been associated with tachycardia, insomnia, nervousness, hypertension, and osteoporosis (6, 7, 8).

Triiodothyroacetic acid (TRIAC) is a physiological metabolite of T3. By a specific immunoassay, it has been detected in blood, and a half-life of around 6–8 h has been determined (9, 10). TRIAC binds to liver nuclear thyroid hormone receptor with an affinity equal to or even higher than that of T3 or T4 (11) and inhibits circulating TSH as efficiently as T3/T4. Because its clearance is faster than that of L-T4, larger and frequent doses of TRIAC are required to achieve the same degree of suppression of TSH (12). Different clinical studies (13, 14, 15, 16) have been performed showing that TRIAC has a rather selective action at the pituitary level, with almost no effects on basal metabolic rate, pulse rate, nitrogen metabolism, and cardiovascular function and therefore is devoid of the drawbacks that presents L-T4 treatment. However, a more recent study (15) has shown that although L-T4 and TRIAC have comparable effects on cardiovascular function, TRIAC is not pituitary selective and has increased hepatic and skeletal thyromimetic actions when compared with L-T4. The present studies were performed to compare the therapeutic effectiveness and possible side effects of the treatment of nontoxic goiter with either L-T4 or TRIAC. Previously Jaffiol et al. (17) have proposed the use of TRIAC in the treatment of nontoxic goiter. However, this is the first report, to our knowledge, of a comparative study between TRIAC and L-T4 in this pathology.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study design

Thirty-six white Caucasian women were finally included in this study. They were referred to the Endocrine Division due to goiter detected by primary care physicians. After an initial work-up, they were prospectively randomized to either L-T4 or TRIAC treatment at TSH suppressive doses for 11 months. All patients belonged to the Buenos Aires metropolitan area and were nonendemic for goiter and iodine sufficient (mean 24-h urinary iodine excretion was ~200 µg).

Entry criteria were: 1) euthyroidism both by clinical and laboratory data; 2) diffuse or nodular goiter (nodular goiter patients had either solitary nodules or multinodular goiter); 3) cytology consistent with a benign or indeterminate lesion by fine needle aspiration (FNA); 4) lack of thyroid hormone treatment for the previous 12 months; 5) nodule size larger than 8 mm with a solid or mixed pattern by ultrasonography (US); 6) cold or warm nodules according to scintigraphy. Exclusion criteria were: 1) FNA compatible with malignancy, chronic thyroiditis, or suspicious material; 2) cystic nodules by US; 3) hot nodules by scintigraphy; 4) diabetes, pregnancy, cardiovascular, liver, or renal diseases; and 5) estrogen or bisphosphonates therapy.

The present protocol was organized according to the guidelines proposed in the Declaration of Helsinki and was approved by the committees of Medical Ethics and Medical Research of the French Hospital of Buenos Aires as well as by the Committee of Pharmacology of the Department of Pharmacology, University of Buenos Aires School of Medicine. Written consent was previously obtained from all patients included.

Protocol

Previous to the start of the treatment (-4 wk) the following parameters were determined: TSH; free T4; total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)-cholesterol; blood glucose; triglycerides; thyroglobulin (Tg); thyroperoxidase (TPO) and Tg antibodies; osteocalcin; and deoxypyridinoline. FNA was performed in nodular goiter to exclude those patients with cytology suspicious of malignancy or thyroiditis. Goiter volume was assessed by three- dimensional sonography. Bone densitometry of lumbar (L2-L4) and femoral neck regions were performed by dual-energy x-ray absorptiometry. Weight (kilograms), mean arterial pressure (millimeters of mercury), and heart rate (beats per minute) were recorded.

At visit 0, the patients were started on either treatment. Patients were reevaluated at 6, 8, 12, 20, 26, 32, and 38 wk. At each visit to the outpatient clinic, the following parameters were assessed: body weight, mean arterial pressure, heart rate, compliance, signs and symptoms of hyperthyroidism, TSH, and free T4. At visits corresponding to 20 and 38 wk, Tg and TPO antibodies; glycemia; Tg; total, HDL, and LDL-cholesterol; triglycerides; osteocalcin; D-pyridinoline, and thyroid US scan were determined. At the end of the study period, a new bone densitometry was obtained. The two groups received a starting dose of either 50 µg/24 h of L-T4 or 350 µg twice daily of TRIAC. The daily doses were increased at each visit until TSH was suppressed to levels below the lower limit of the normal reference range. The L-T4 capsules contained 50, 100, or 150 µg and could be tailored according to needs. The TRIAC preparations contained 350 µg (TRIACANA, Sidus Labs, Buenos Aires, Argentina).

In a subgroup of patients (12 women under TRIAC and 11 women under L-T4), circulating SHBG, homocysteine, apoproteins A1 (Apo A) and B (Apo B) were also evaluated at baseline and after 6 months of treatment.

Measurements

All determinations were performed by a chemist and radiologist who were blind to the patients treatment assignment.

Laboratory evaluation

Plasma TSH was measured by chemiluminescence (DPC Immulite, Los Angeles, CA); plasma free T4 by chemiluminescence (DPC Immulite). The reference values were: TSH 0.3–5.0 µU/ml and free T4 0.8–2.0 ng/dl. Autoantibodies against TPO and Tg were determined by chemiluminescence (DPC Immulite). Thyroglobulin was assessed by chemiluminescence (DPC Immulite). Glycemia was measured by an enzymatic test (Roche Diagnostics, Indianapolis, IN). Normal values were: 76–120 mg/dl. Lipids were measured as follows: total cholesterol, CHOD-PAP enzymatic test (Roche Diagnostics); LDL-cholesterol by turbidimetric test (Roche Diagnostics); HDL-cholesterol by precipitation enzymatic test (Roche Diagnostics); triglycerides by color enzymatic test (Roche Diagnostics); plasma Apo A and B by immunoturbidimetric method (developed with INCSTAR antibodies, Stillwater, MN); SHBG by immunoradiometric assay (DPC Immulite); homocysteine by fluroscein polarization immunoassay (Abbott Diagnostics, Abbott Park, IL). Normal values were: total cholesterol, 130–200 mg/dl; LDL-cholesterol, less than 150 mg/dl; HDL-cholesterol, females over 45 mg/dl; triglycerides, less than 200 mg/dl; plasma Apo A, 112–152 mg/dl; plasma Apo B, 70–96 mg/dl; SHBG, 16–120 nM/liter; and homocysteine, 5–12 mM/liter. Osteocalcin was determined by chemiluminescence (DPC Immulite. D-Pyridinoline was also determined by chemiluminescence (DPC Immulite); normal values are 2–12 ng/ml and 2.3–7 nM pyridinoline/mM creatinine, respectively.

Bone mineral density (BMD)

Bone densitometry of lumbar spine and femoral neck were assessed by dual-energy x-ray absorptiometry with a densitometer (QDR-4500A, Hologic, Waltham, MA). The coefficient of variation for the measurement of lumbar spine is 1.6% and for femoral neck is 2%.

Thyroid scintigraphy

Was performed after a tracer dose of 5 mCi 99mTc, using a {gamma}-camera single-photon emission-computed tomography (Elscint, Apex SPX, Haifa, Israel) with a low-energy all-purpose collimator and zoom 2.

US scan

Total thyroid volume, for diffuse goiters, and nodular volume, for nodular goiter, were calculated after three-dimensional US measurement, using the formulae of the ellipsoid (18): volume (ml) = {pi} 6 x L x W x T, where L is length, W is width, and T is thickness. For multinodular goiters, the volume of each of the palpable nodules was determined, and only the addition of the different volumes within one patient was considered. An Aloka echo camera (SSD-500, Tokyo, Japan) US scanner equipped with a linear 7.5-mHz probe was used.

Cytological examination of the nodules

FNA was performed as previously described (19). Cytologic characteristics were evaluated by the same cytologist.

Statistical analysis

Percentage changes in nodule volumes (sum of volumes for patients with multiple nodules) from the baseline assessment to the end of the drug intervention period were analyzed by paired t test for each treatment group. These relative size changes were compared between the two groups: TRIAC vs. L-T4 by Student’s t test. The rest of the parameters analyzed in the study were compared in a similar way. Fisher’s exact test was used to compare the proportion of goiters that exhibited more than 50% reduction between both groups. Fisher’s exact test was also used to compare the incidence of adverse effects. Results are expressed as mean SD unless otherwise stated. A P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical and thyroid function data

Nineteen women aged 48 ± 12 yr were randomly assigned to the TRIAC group. In this group, two diffuse goiters and 23 nodules were detected. The maximum diameter of the nodules ranged from 9.7–35 mm. Three patients were ATPO positive (none with diffuse goiter). The mean dose of TRIAC required to maintain TSH levels suppressed was 19.6 µg/kg·24 h, an average of 1400 µg/24 h in two doses.

In the L-T4 group, 17 women were assigned: Three diffuse goiters and 16 nodules were found. Five patients were ATPO positive (none with diffuse goiter). The mean dose of L-T4 required was 1.7 µg/kg·24 h, which averaged 110 µg daily.

Besides the 36 patients who finished this study, eight patients that had completed the baseline evaluation refused to participate in the study, withdrawing their consent, and two patients dropped out of the study. One became pregnant and the other was found with increased levels of mean arterial pressure (in the L-T4 group).

The mean body mass indexes were 28.9 ± 7.31 kg/m2 for the TRIAC group and 25 ± 5.5 kg/m2 for the L-T4 group (P = 0.08) at baseline. After 11 months of treatment, the TRIAC group reduced weight significantly (from 74.2 ± 18 to 71 ± 19 kg, P < 0.05), whereas the L-T4 group remained stable (from 64 ± 12 to 65 ± 10 kg, ns) (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical, biochemical, ultrasonographic, and densitometric parameters before and after 11 months of treatment with TRIAC or L-T4

 
TSH levels decreased from 1.9 ± 1.6 to 0.18 ± 0.1 U/ml in the TRIAC group and from 2.1 ± 2.5 to 0.18 ± 0.3 U/ml in the L-T4 group (Table 1Go). Both treatments achieved a similar degree of TSH inhibition throughout the study period after 4–8 wk.

Free T4 levels were reduced as expected with TRIAC from 1.3 ± 0.3 to 0.51 ± 0.2 ng/dl (P < 0.01) and increased within the normal range of reference in the L-T4 group (1.4 ± 0.2 ng/dl to 1.8 ± 0.5 ng/dl (P < 0.01). Thyroglobulin levels showed nonsignificant variation from 31 ± 25 to 25.5 ± 20 ng/ml and from 22 ± 24 to 21 ± 21 ng/ml in the TRIAC and L-T4 groups, respectively (Table 1Go). No significant correlation could be determined between the degree of decrease in circulating Tg and the decrease in goiter size (not shown). No significant changes from baseline values were observed in blood glucose in the two groups.

Goiter volume changes

Starting goiter volume decreased significantly from 4.8 ± 4.9 to 2.59 ± 2.0 ml in the TRIAC group (P < 0.01) and from 5.1 ± 4.8 to 4.3 ± 4 ml in the L-T4 group (ns) after 11 months of treatment (Table 1Go). There was a marked reduction of goiter volume in the TRIAC patients of 37.9 ± 35.4% vs. 14.5 ± 39.5% in the L-T4 group (P = 0.08). This difference was observed only after 11 months of treatment (Fig. 1Go). Forty-two percent of the goiters in the TRIAC group (8 of 19) reduced more than 50% their initial volume. Only 17.7% (3 of 17) did so in the L-T4 group. When these proportions were compared between the two groups, according to the Fisher’s exact test, this numerical difference in proportions (2-fold) did not achieve statistical significance (P = 0.15).



View larger version (10K):
[in this window]
[in a new window]
  		FIG. 1. Variations of goiter volume with time of treatment (top). Changes (%) in goiter volume after treatments (bottom). Data are expressed as mean ± SEM.

 
Clinical cardiovascular parameters

Basal heart rates were similar: 79.5 ± 9 beats/min in the TRIAC patients and 79.6 ± 1 beats/min for the L-T4 group. This parameter did not differ at the end of the study: 80.7 ± 8.6 beats/min for TRIAC and 82.9 ± 9 beats/min for L-T4 or when the change from baseline in each group was compared. Similar findings were observed for the mean arterial pressure, which varied from 93 ± 10 to 89 ± 13 mm Hg in the TRIAC group and from 92 ± 10 to 90.4 ± 9 mm Hg in the L-T4 group (Table 1Go).

Hepatic parameters

A significant decrease (P < 0.05) in total cholesterol (from 211 ± 42 to 188 ± 38 mg/dl) and LDL-cholesterol levels (from 143 ± 35 to 109 ± 31 mg/dl) after 11 months of treatment was seen in the TRIAC group. In the L-T4 group, total cholesterol levels varied from 225 ± 48 to 226 ± 46 mg/dl and LDL cholesterol levels from 148 ± 33 to 137 ± 32 mg/dl in a nonsignificant way. However, when changes from baseline were compared between the two groups, the differences were not significant. The same findings were observed for the HDL cholesterol and triglyceride plasma levels (Table 1Go and Fig. 2Go).



View larger version (15K):
[in this window]
[in a new window]
  		FIG. 2. Changes (%) in lipid profile. CHOL, Total cholesterol; HDL, HDL cholesterol; LDL, LDL cholesterol; TRIG, triglycerides. Data are expressed as mean ± SEM.

 
In a subgroup of the same cohort of patients, comprising 23 women, 12 assigned to TRIAC and 11 to L-T4, Apo A and B, homocysteine, and SHBG levels were also assessed after 6 months of treatment. Both groups showed similar weight reduction, -0.9 ± 2.3% (TRIAC) vs. -0.93 ± 1.5% (L-T4 group). SHBG levels increased similarly in both groups when changes from baseline were analyzed: TRIAC 92 ± 107%, L-T4 57 ± 87% (ns). Homocysteine levels increased 4 ± 14% under TRIAC and decreased 1.3 ± 14% under L-T4. Changes in Apo A levels did not differ between the groups either: TRIAC 12.5 ± 13.0% and for L-T4 4.24 ± 9.0% (ns). However, Apo B levels decreased in a significantly higher proportion in the TRIAC group (12.6 ± 12%) than in the L-T4 group (0.4 ± 14%) (P < 0.05).

Bone metabolism

Serum osteocalcin increased nonsignificantly from 6.9 ± 4.8 to 7.47 ± 4 ng/ml in the TRIAC group and from 5.7 ± 2.5 to 6.2 ± 5.4 ng/ml in the L-T4 group. When the changes in both groups were compared (36.7 ± 123% TRIAC and 13 ± 91% L-T4), they did not differ either.

In terms of bone reabsorption, deoxypyridinoline levels showed a significant increase from baseline in the TRIAC group (8.6 ± 3.1 ng/ml to 13.9 ± 3.9 ng/ml, P < 0.05 and from 9.6 ± 4.9 to 10.4 ± 3.5 ng/ml in the L-T4 group, ns). The increase was similar for both groups (85.7 ± 95% TRIAC and 52.9 ± 75%, L-T4).

Mean BMD at L2-L4 spine in the TRIAC and L-T4 groups did not vary significantly from baseline: 974.3 ± 176 to 967 ± 172 g/cm2 TRIAC and 997 ± 140 to 972 ± 120 g/cm2 L-T4, exhibiting a similar nonsignificant decrease of 0.81 ± 5.6% (TRIAC) and 2.38 ± 7.1% (L-T4). At the femoral neck, however, BMD decreased significantly in the TRIAC group, from 806 ± 132 to 767 ± 141 g/cm2 (-4.5 ± 2.5%; P < 0.01). In the L-T4-treated patients, BMD fell from 759 ± 121 to 737 ± 73 g/cm2 (-2.07 ± 7.74%). When these proportions were compared by Student’s t test, the difference was nonsignificant (P = 0.3) (Table 1Go and Fig. 3Go).



View larger version (18K):
[in this window]
[in a new window]
  		FIG. 3. Changes (%) in BMD of lumbar spine and femoral neck. Data are expressed as mean ± SEM.

 
Adverse events

Table 2Go shows the frequency of adverse events in both groups under treatment. As indicated, the incidence of adverse events was significantly higher in the L-T4 patients, compared with the TRIAC group (P < 0.01).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Comparative adverse effects of TRIAC and L-T4

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present results provide, for the first time, a comparison of the therapeutic efficacy between L-T4 and TRIAC in nontoxic diffuse and nodular goiter. Both treatments caused a similar degree of inhibition of circulating TSH and a decrease in goiter volume. Due to the shorter half-life of TRIAC, total daily dose was distributed into two intakes. Previous studies have shown that the TSH inhibition of a single oral dose of 1050 µg TRIAC will last at least 12 h (10). With TRIAC treatment the shrinkage in goiter size was more important when compared with L-T4. The proportion of patients who reduced their goiter size by 50% or more was 42% for the TRIAC-treated patients, compared with 17% in the L-T4-treated cohort. Many reports have communicated different degrees of success with L-T4 treatment in this kind of patient. A very wide variation in the percentage of responses to L-T4 treatment has been observed, ranging from 0–50% (20, 21). However, the efficacy of the treatment with TRIAC has not yet been so extensively explored.

As expected, TRIAC administration caused a significant drop in circulating free T4, whereas L-T4 treatment increased its values, albeit within normal limits. The dose of TRIAC used in the present studies contained around 800 µg iodine. Previous studies have indicated that this amount is capable of causing some decrease of goiter size in patients from an endemic goiter area (22, 23). However, the sensitivity of the gland to inhibitory doses of iodine is inversely related to its endogenous iodine content (24). Because all our patients live in a nonendemic area and have a normal iodine supply, we may therefore conclude that the iodine released from the TRIAC molecule may have only a small marginal effect in goiter shrinkage. Moreover, an essential part of TRIAC is cleared in the bile, and this iodine will not be available to the iodide pool.

Despite the many studies performed, the pathogenesis of nontoxic goiter remains elusive. The results obtained by suppressing circulating TSH as well as the experimental work showing the effect of TSH in thyroid cell proliferation (25) would indicate that this hormone may play a role. However, other studies (26, 27) have pointed out that other factors may also participate in the regulation of this process. This would partially explain the lack of complete success of the treatments based on TSH inhibition. Previous results from different laboratories, including ours, have shown that iodothyronines can affect in vitro several thyroid parameters (28, 29). This indicates that these compounds have, besides the well-known action at the pituitary level, a direct effect on the thyroid gland. Moreover, T3 receptors have been found in the thyroid gland (30, 31), thus supporting this view. We have previously shown that both L-T4 and TRIAC inhibit RNA synthesis in calf thyroid slices (28). The reason TRIAC proved to induce better results than L-T4 in the present studies remains purely speculative. Because both L-T4 and TRIAC caused a similar degree of TSH inhibition, this cannot be offered as an explanation. As already mentioned, early studies on liver nuclear receptor binding have shown that TRIAC can bind with even greater affinity than L-T3 (11). No data concerning the comparative binding of L-T4, L-T3, and TRIAC on thyroid nuclear receptors are available. Because distinct isoforms of receptors are present in different tissues, it may be speculated that the better results present herein might be due to a selective binding of TRIAC to one of those isoforms. However, this hypothesis requires further studies.

The present protocol sought to suppress but not totally inhibit circulating TSH. Special care was taken concerning the levels of free T4, which remained within normal limits in the L-T4 group. Therefore, it is not unexpected that both treatments showed almost similar effects on bone metabolism. However, a nonsignificant trend suggested that the decrease in bone densitometry was more frequent among the TRIAC-receiving patients. According to controlled cross-sectional studies concerning the impact of L-T4 on BMD, it has been demonstrated that suppressive doses are often associated with significant bone loss in postmenopausal women (32). Because the dose of L-T4 used in this study intended to suppress but not inhibit completely circulating TSH, no significant effects on bone metabolism were observed. However, in the patients treated with TRIAC, the hip BMD fell significantly, but when compared with the change observed from baseline in the L-T4 group, the difference was nonsignificant. It is difficult to draw a conclusion from the present findings because the cohort of patients analyzed included both pre- and postmenopausal women.

No significant changes were observed in both groups under treatment in glycemia or triglycerides. A slight but significant decrease was observed in total and LDL-cholesterol after TRIAC, without significant changes under L-T4. Conversely, HDL-cholesterol also showed a slight but significant increase under L-T4 and remained unchanged under TRIAC. Nevertheless, these changes, when a comparison between the two groups was performed, did not exhibit significant differences. These findings are in contrast with those reported by Sherman and Ladenson (15). This could be due to differences in the population under study, which was, in their case, a group of thyroidectomized cancer patients, whereas the subjects in this study were euthyroid. Besides, the doses of L-T4 and TRIAC employed by these authors were 60% higher than those used in our study. However, in the subgroup in which Apo B could be determined, we found a significant decrease under TRIAC, suggesting a more marked effect on liver metabolism. These results agree with those reported by Sherman and Ladenson (15) and would indicate that Apo B is a very sensitive peripheral marker of TRIAC action.

It has been proposed that the decrease in circulating Tg could have a predictive value concerning the reduction of goiter size under TSH inhibition (33). However, the present results do not support this assumption and agree with previous similar data (34).

Finally, and confirming many previous studies, L-T4 administration was more frequently associated with adverse events than TRIAC treatment. In this regard it should be mentioned that the association of L-T4 plus TRIAC in the suppression of circulating TSH in thyroidectomized cancer patients proved to cause fewer side effects than L-T4 as a sole treatment (35, 36).

In conclusion, under the present protocol, TRIAC demonstrated its efficacy as a goiter shrinkage agent. When compared with L-T4, the action appeared to be more important in the reduction of goiter size, although it did not attain a significant level. Besides, it was associated with a relative advantage concerning a significant lower incidence of adverse events. In terms of hepatic and bone metabolism, TRIAC and L-T4 had comparable effects. Therefore, TRIAC provides an alternative for the treatment of nontoxic diffuse and nodular goiter.


   Footnotes
 
This work was supported in part by a grant from the Secretary of State of Science and Technology and the University of Buenos Aires. M.A.P. is an established researcher of the National Research Council of Argentina.

Abbreviations: Apo A, Apoprotein A1; Apo B, apoprotein B; BMD, bone mineral density; FNA, fine needle aspiration; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Tg, thyroglobulin; TPO, thyroperoxidase; TRIAC, triiodothyroacetic acid; US, ultrasonography.

Received January 22, 2003.

Accepted August 6, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Gharib H, Mazzaferri EL 1998 Thyroxine suppressive therapy in patients with nodular disease. Ann Int Med 18:386–394
  2. Paggi A, Persegani-Trimarchi C, Russo P, Mastropasqua M, Mosetti MA, Losi T, Leri O 1999 Solitary nodular disease and multinodular goiter: a retrospective study on suppressive versus replacement levothyroxine therapy. Endocr Res 25:229–238[Medline]
  3. Reverter JL, Lucas A, Salinas I, Audi L, Foz M, Sanmarti A 1992 Suppressive therapy with levothyroxine for solitary thyroid nodules. Clin Endocrinol (Oxf) 38:25–28
  4. Gullu S, Gurses A, Baskal N, Uysal AR, Kamel AN, Erdogan G 1999 Suppressive therapy with levothyroxine for euthyroid diffuse and nodular goiter. Endocr J 46:221–226[Medline]
  5. Zelmanovitz F, Genro S, Gross JL 1998 Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analysis. J Clin Endocrinol Metab 83:3881–3885[Abstract/Free Full Text]
  6. Faber J, Galloe AM 1998 Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a metaanalysis. Eur J Endocrinol 130:350–356
  7. Toivonen J, Tahtela R, Laitinen K, Risteli J, Valimaki MJ 1998 Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy. Eur J Endocrinol 138: 667–673
  8. Taimela E, Taimela S, Nikkanen V, Irjala K 1994 Accelerated bone degradation in thyroid carcinoma patients during thyroxine treatment, measured by determination of the carboxy terminal telopeptide region of type I collagen in serum. Eur J Clin Chem Clin Biochem 32:827–831[Medline]
  9. Nakamura Y, Chopra I, Solomon DH 1978 An assessment of the concentration of acetic and propionic acid derivatives of 3,5,3'-triiodothyronine in human serum. J Clin Endocrinol Metab 46:91–97[Medline]
  10. Menegay C, Juge C, Burger AG 1989 Pharmacokinetics of 3,5,3'-triiodothyroacetic acid and its effects on serum TSH levels. Acta Endocrinol 121:651–658
  11. Evans RW, Braverman LE 1986 Use of 125I-triiodthyroacetic acid to measure nuclear thyroid hormone receptor. Endocr Res 12:37–47[Medline]
  12. Burger AG, Engler D, Sakoloff C, Staheli V 1979 The effects of tetraiodothyroacetic and triiodothyroacetic acids on thyroid function in euthyroid and hyperthyroid subjects. Acta Endocrinol 92:455–467
  13. Bracco D, Morin O, Schutz Y, Liang H, Jequier E, Burger AG 1993 Comparison of the metabolic and endocrine effects of 3,5,3'-triiodothyroacetic acid and thyroxine. J Clin Endocrinol Metab 77:221–228[Abstract]
  14. Medeiros-Neto G, Kallas WG, Knobel M, Cavaliere H, Mattar E 1980 Triac (3,5,3'-triiodothyroacetic acid) partially inhibits the thyrotropin response to synthetic thyrotropin releasing hormone in normal and thyroidectomized hypothyroid patients. J Clin Endocrinol Metab 50:223–225[Abstract]
  15. Sherman SI, Ladenson PW 1992 Organ-specific effects of tiratricol: a thyroid hormone analog with hepatic non-pituitary superagonist effects. J Clin Endocrinol Metab 75:901–905[Abstract]
  16. Lind P, Langsteger W, Koltringer P, Eber O 1989 3,5,3'triiodothyroacetic acid (TRIAC) effects on pituitary thyroid regulation and on peripheral tissue parameters. Nuklearmedizin 28:217–220[Medline]
  17. Jaffiol C, Baldet L, Papachristou C, Bringer J 1988 Interet de l’acide triiodthyroacetique comme traitment freinateur de la secretion thyreotrope en pathologie thyroidienne. Presse Med 17:57–60
  18. Brunn J, Block U, Ruf G, Bos I, Kunze WP, Scriba PC 1981 Volumetric analysis of thyroid lobes by real-time ultrasound. Dtsch Med Wochenschr 106:1338–1340[Medline]
  19. Brenta G, Schnitman M, Bonnahon LA, Besuschio S, Zuk CA, De Barrio G, Peruzzotti CH, Saubidet AG 2002 A simple skin marking technique as an option to optimize ultrasound guided thyroid nodules. Endocr Pract 8:5–9
  20. Castro RM, Caraballo PJ, Morris JC 2002 Effectiveness of thyroid hormone suppressive therapy in benign solitary thyroid nodules: a meta-analysis. J Clin Endocrinol Metab 87:4154–4159[Abstract/Free Full Text]
  21. Gharib H, James EM, Charboneau WJ, Naessens JM, Offord KP, Gorman CA 1987 Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study. N Engl J Med 317:70–75[Abstract]
  22. Hintze G, Emrich D, Kobberling J 1989 Treatment of endemic goitre due to iodine deficiency with iodine, levothyroxine or both: results of a multicentric trial. Eur J Clin Invest 19:527–534[Medline]
  23. Einenkel D, Bauch KH, Nenker G 1992 Treatment of juvenile goitre with levothyroxine, iodine or a combination of both: the value of ultrasound grey-scale analysis. Acta Endocrinol (Copenh) 127:301–306[Medline]
  24. Krawiec L, Chazenbalk GD, Puntarulo S, Burton G, Boveris A, Valsecchi RM, Pisarev MA 1988 The inhibition of PB 125I formation in calf thyroid caused by 14-iodo-15-hydroxy-eicosatrienoic acid is due to decreased H2O2 availability. Horm Metab Res 20:86–91[Medline]
  25. Kimura T, van Keymeulen A, Golstein J, Fusco A, Dumont JE, Roger PP 2001 Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocr Rev 22:631–656[Abstract/Free Full Text]
  26. Studer H, Derwahl M 1995 Mechanism of nonneoplastic endocrine hyperplasia-A changing concept: a review focused on the thyroid gland. Endocr Rev 16:411–426[Abstract]
  27. Derwahl M, Broecker M, Kraiem Z 1999 Thyrotropin may not be a dominant growth factor in benign and malignant thyroid tumors. J Clin Endocrinol Metab 84:829–834[Free Full Text]
  28. Juvenal GJ, Pisarev MA, Kleiman de Pisarev DL, Altschuler N 1981 Uptake, metabolism and action of triiodothyronine in calf thyroid slices. Mol Cell Endocrinol 22:31–40[Medline]
  29. Kleiman de Pisarev DL, Juvenal GJ, Pisarev MA 1978 Action of KI and several iodocompounds on 3H-uridine incorporation into thyroid RNA. Acta Endocrinol (Copenh) 89:316–322[Medline]
  30. Pisarev MA, Juvenal GJ, Kleiman de Pisarev DL, Chazenbalk GD, Krawiec L, Valsecchi RM 1986 Subcellular localization and binding of 125I-triiodothyronine in calf thyroid. Horm Metab Res 18:318–322[Medline]
  31. Erkenbrack DE, Rosenberg LL 1986 Binding of thyroid hormones to nuclear extracts of thyroid cells. Endocrinology 119:311–317[Abstract]
  32. 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[Abstract]
  33. Morita T, Tamai H, Oshima A 1989 Changes in serum thyroid hormone, thyrotrophin and thyroglobulin concentrations during thyroxine therapy in patients with solitary thyroid nodules. J Clin Endocrinol Metab 69:227–230[Abstract]
  34. Burgi U, Scazziga BR, Rosselet PO, Burgi H, Studer H 1988 Can serum thyroglobulin predict the effect of thyroid hormone therapy on goiter growth? Acta Endocrinol 119:118–124
  35. Muller Gartner HW, Schneider C 1988 3,5,3'triiodothyroacetic acid minimizes the pituitary thyrotropin secretion in patients on levo-thyroxine therapy after ablative therapy for differentiated thyroid carcinoma. Clin Endocrinol 28: 345–351
  36. Jaffiol C, Daures JP, Nsakala N, Guerenova J, Baldet L 1995 Le controle a long terme du traitment médicale du cancer thyroidiene différencié. Ann Endocrinol (Paris) 56:119–126[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brenta, G.
Right arrow Articles by Pisarev, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brenta, G.
Right arrow Articles by Pisarev, M. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals