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BRIEF REPORT |
Department of Medicine, Division of Endocrinology, University of Patras Medical School, Patras 24500, Greece
Address all correspondence and requests for reprints to: Apostolos G. Vagenakis, M.D., Department of Medicine, University Hospital, Rion Patras 26500, Greece. E-mail: vagenak{at}otenet.gr.
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Abstract |
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Objective: To determine whether, in human thyroid, administration of large doses of iodine for a relatively long time results in alterations of intrathyroidal hormonal (HI) T4 and T3 and total iodine (TI) content, as well as whether changes in serum concentration of thyroid hormones and TSH would occur after iodine administration or discontinuation.
Design: In 33 euthyroid patients with single thyroid nodule or hyperparathyroidism, Lugol solution (80 mg iodine) was administered for 15 d before operation. Groups of six to eight patients underwent operation 0, 5, 10, and 15 d after iodine withdrawal. TI, HI in a sample of thyroid tissue, and serum concentration of T4, T3, and TSH were measured. In 21 normal euthyroid subjects who did not undergo operation, a similar protocol was used and serial blood measurements were taken.
Main Outcome Measure: Intrathyroidal TI, HI, and serum thyroid hormone and TSH measurements were the main outcome measure.
Results: Intrathyroidal HI content and serum T4 and T3 were unchanged during and after iodine discontinuation. TI was increased during iodine administration and returned to control values 5 d after discontinuation of iodine. The ratio of HI/TI was decreased and returned to control values 15 d after the iodine was discontinued. Serum TSH was increased during iodine administration and returned to control values 10 d after iodine withdrawal.
Conclusions: In humans, administration of iodine for a relatively long period of time was accompanied by increased intrathyroidal TI, but no changes in HI or demonstrable increases of serum T4 and T3 were observed. It is hypothesized that the maintenance of normal intrathyroidal HI is the result of the combined inhibitory effect of iodine on thyroid hormone synthesis and on the release of T4 and T3 from the thyroid.
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Introduction |
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Recent studies in rats (3) confirmed earlier observations (1) suggesting that the thyroidal sodium/iodine symporter mRNA and protein expression is decreased in rats exposed to large doses of iodine in an attempt by the thyroid to decrease the intrathyroidal concentration of iodine.
In humans little is known about the intrathyroidal content of iodine as well as of T4 and T3 after chronic exposure of large quantities of iodine. In one study the total intrathyroidal iodine content was increased after exposure to radiocontrast media, but intrathyroidal T4 and T3 were not affected (4). It is unclear whether the mechanism(s) of thyroid autoregulation are similar in humans and animals, and there is no direct evidence in humans that the intrathyroidal hormonal iodine is decreased or increased by excess iodine.
In this study, humans were exposed to large doses of iodine for relatively long period of time to observe, by direct estimation of total and hormonal intrathyroidal iodine content, whether adaptation had occurred as well as the serum concentration of TSH and thyroid hormones during and after iodine withdrawal.
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Patients and Methods |
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Eight patients were used as untreated controls. In the remaining patients, 80–100 mg of iodide (Lugol solution) was administered daily for 15 d. Seven patients were operated the last (d 15) day on iodine and the remaining patients were divided in groups of six or seven and underwent operation at 5, 10, and 15 d after iodine discontinuation. Iodine in urine was measured before and the day of iodide withdrawal to verify compliance. The day of operation, blood samples were obtained for T3, T4, and TSH measurement.
Twenty-one normal volunteers (group B) who did not undergo operation were also studied. Serum thyroid hormones and TSH were measured before and the last day (d 15) on iodine administration, and 5, 10, 15, and 20 d after iodine withdrawal.
Methods
Two pieces of thyroid tissue, 200 mg each, were obtained from different areas of the normal thyroid gland and were stored deep frozen (–70 C) until analyzed in duplicate samples. Thyroid tissue was pulverized in liquid nitrogen and homogenized in 2 ml of cold (4 C) buffer saline (pH 7.6).
From the homogenate one aliquot containing 40 mg tissue was digested with 240 U of pronase in buffered saline. The reaction tubes were charged with nitrogen and incubated for 16 h in a shaking water bath at 37 C (5). The hydrolysis was followed by the T4 and T3 extraction. One aliquot of the digests was extracted with ethanol-butanol (1:1) and centrifuged at 2000 x g for 10 min.
The supernatants were diluted with 70% ethanol, and several aliquots were dried under nitrogen and were reconstituted with zero standard of T3 and T4, respectively. The reconstitutes were assayed for T3 and T4 by an Abbott IMX semiautomatic analyzer.
Total tissue iodine determination.
Intrathyroidal iodine was measured in duplicate by photometry (6), based on the catalytic effect of iodine in the redox reaction 2Ce (IV) + As (III)
2C (III)+As(V).
The concentration of iodine calculated by this way represents total iodine (TI). The amount of iodine in intrathyroidal T4 and T3 was considered as hormonal iodine (HI).
The tissue concentration of T3, T4, and TI was expressed as µg/g tissue as well as µg/g protein. Serum free T3, free T4, T4, T3, and TSH were measured by an Abbott IMX semiautomatic analyzer.
Informed consent was obtained from all participants, and the study was approved by the Hospital’s Ethics Committee.
Statistics. Independent t test with and without log transformation was applied for detecting the difference that existed among the means of various parameters in the different times after iodide withdrawal compared to control group, whereas ANOVA with Bonferroni’s t test was used in group B. Correlations were analyzed using the Spearman correlation coefficient (two-tailed significance). All statistics were performed using SPSS for windows, version 9.0.1 (SPSS, Chicago, IL).
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Results |
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Group AC.
TI in the controls who did not receive iodine was 429 ± 226 µg/g tissue (mean ± SD) and the HI 199 ± 81 µg/g tissue, whereas the ratio of hormonal / total iodine (HI/TI) was 0.52 ± 0.15. Intrathyroidal concentration of T3 and T4 were 18 ± 7 and 291 ± 118 µg/g tissue, respectively, as shown in Table 1
. Similar results were obtained when intrathyroidal concentration of T3 and T4 were expressed in µg/g protein.
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Intrathyroidal content of T3 and T4 and serum T3 and T4 concentrations were similar to controls, whereas serum TSH concentration was higher compared with controls (P = 0.021, t = –2.655).
Group A5.
TI and HI content (5 d after iodide withdrawal) were 666 ± 552 and 278 ± 158 µg/g tissue, respectively, and were similar to controls. The ratio HI/TI showed a significant decrease in respect to control group (P = 0.05, t = 2.150). No differences were observed in the intrathyroidal concentration of T3 and T4 compared with control group (Table 1
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Serum TSH levels were decreased compared with control group (P = 0.015, t = 2.789), whereas no differences were observed in serum T3 and T4 concentrations.
Group A10. Ten days after iodide withdrawal, TI was 471 ± 124 and the ratio HI/TI continued to be lower compared with control group (P = 0.016, t = 2.812). No differences were observed in intrathyroidal content of T3 and T4, as well as in serum TSH, T3, and T4 concentrations compared with the control group.
Group A15. Fifteen days after iodide withdrawal, TI, HI, the ratio HI/TI, as well as intrathyroidal concentrations of T3 and T4 were similar to the control group.
No differences were observed in serum TSH and T3 compared with the control group, while serum T4 showed a small increase (P = 0.026, t = –2.569).
Inspecting the data of group Ac, a linear correlation was observed between TI content and intrathyroidal T4 and T3 content (r = 0.852, P = 0.007; and r = 0.688, P = 0.05, respectively). This correlation was lost in the subsequent groups, which received the iodine.
Nonoperated volunteers (group B)
Serum TSH concentration the 15th day on iodine administration showed an increase compared with values obtained before the administration of iodine (P < 0.001, F = 24.541). Serum values of T4, T3, FT4, and FT3 did not change compared with values obtained before iodine administration (Table 2).
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Discussion |
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Previous studies have showed that when rats were exposed chronically to large quantities of iodine, the TI was increased and, although the rate of T4 and T3 formation was increased, the thyroidal content of T4 and T3 remained unaltered compared with noniodine-treated rats (7).
It is difficult to explain why the increased rate of T4 and T3 formation did not lead to increased T4 and T3 content. It was assumed that an increased amount of nonhormonal iodide escapes from the thyroid after the exposure due to the formation of noncalorigenic iodinated compounds (8, 9).
In the present study in humans, the TI content was increased only during the iodine administration but returned rapidly to control values after the discontinuation of iodine, and remained unaltered thereafter. The HI content did not change throughout the time period of iodine administration. These findings are in concordance with those reported in rats.
The serum values of T4 and T3 on d 15 of continued iodine administration, however, were not in concordance with the intrathyroidal events. As expected, serum TSH was increased and T4, T3, and free T4 were lower in the iodine-treated group (d 15 on iodine), although the decrease did not reach statistical significance. Thus, the increase in TSH may be explained by the small decrease of T4 and T3 due to the inhibitory effects of iodine on the release mechanism(s) of T4 and T3 (10, 11, 12, 13).
A plausible explanation why the HI was not altered could be the combination of the small intrathyroidal inhibitory effect of iodine on hormone synthesis, pari passu with the inhibitory effects of iodine on the release mechanism(s) of T4 and T3, resulting in unaltered intrathyroidal hormonal content. This is consonant with the fact that the serum concentration of thyroid hormones after the discontinuation of iodine did not increase in such levels to be clearly demonstrable by the conventional methods of measuring serum thyroid hormones, but indirectly by the action in the pituitary by decreasing the slightly elevated serum TSH. The direct measurement of HI and the unaltered serum thyroid hormones concentration is in favor of this explanation. Had the iodine resulted in excessive thyroid accumulation of T4 and T3 as a result of uninhibited iodinations simultaneously with the blockade on the release mechanism of T4 and T3, a "burst" of increased amounts of serum T4 and T3 secretion would have been observed. The latter has been shown in patients with iodine-induced thyrotoxicosis after the withdrawal of iodine, which was the consequence of continued intrathyroidal iodinations resulting in an excessive release of T4 and T3, when the blockade of iodine on thyroglobulin proteolysis was removed (10).
In conclusion, in the normal human thyroid gland, the effects of relatively long exposure to large quantities of iodine are similar to those observed in animals. The increased TI content does not result in excessive formation of T4 and T3. We hypothesize that the maintenance of constant quantities of HI is the result of a slight decrease of T4 and T3 synthesis simultaneously with the inhibitory effects on thyroglobulin proteolysis induced by the excess of iodine.
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Acknowledgments |
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Footnotes |
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First Published Online October 17, 2006
Abbreviations: HI, Hormonal iodine; TI, total iodine.
Received June 1, 2006.
Accepted October 5, 2006.
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References |
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