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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4719-4724
Copyright © 2007 by The Endocrine Society

Impaired Iodide Organification in Autonomous Thyroid Nodules

Rodrigo Moreno-Reyes, Bich-Ngoc-Thanh Tang, Alain Seret, Serge Goldman, Chantal Daumerie and Bernard Corvilain

Departments of Nuclear Medicine (R.M.-R., B.-N.-T.T., S.G.) and Endocrinology (B.C.), Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; Experimental Medical Imaging (A.S.), Department of Physics, Université de Liège, 4000 Liège, Belgium; and Department of Endocrinology (C.D.), Université Catholique de Louvain, 1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Rodrigo Moreno-Reyes, Hopital Erasme, Université Libre de Bruxelles, route de Lennik 808, 1070 Brussels, Belgium. E-mail: rmorenor{at}ulb.ac.be.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The clinical evolution of autonomous thyroid nodules (ATN) is unpredictable, and thyrotoxicosis is observed at variable nodule size. In vitro data suggest that hydrogen peroxide production is decreased in ATN, indicating intranodular iodide organification impairment.

Objective: We aimed to determine iodide organification efficiency in ATN and its relationship with thyroid status in patients.

Design: Forty-six patients with a single ATN on the 123I thyroid scan were included in the study. Biological evaluation and iodine perchlorate (I-ClO4) discharge test were carried out in all subjects.

Setting: The study took place at an academic hospital.

Results: Among the 46 patients, 28 patients (61%) had a positive I-ClO4 discharge test with a mean ± SD value of discharge of 42 ± 13%, and 18 (39%) had a negative discharge test with mean ± SD of 5 ± 9%. In the group of patients with a negative discharge test but not in the group with a positive test, serum-free T3 and free T4 concentrations were significantly correlated with the 123I uptake. The severity of hyperthyroidism was not different between both groups.

Conclusions: Intranodular iodide organification was impaired in most patients with ATN. Whether differences in organification capability could predict the risk for evolution to overt hyperthyroidism in patients with ATN remains to be established.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AUTONOMOUS THYROID NODULE (ATN) adenomas are benign monoclonal tumors characterized by their capacity to grow and produce T4 and T3 independently of TSH regulation (1). Hyperthyroidism is infrequent in patients with adenomas less than 2.5 cm in diameter or less than 5 ml in volume, i.e. one half the normal thyroid volume. However, some patients are thyrotoxic with a nodule of less than 2.5 cm in diameter, whereas some are not with a nodule twice this size (2). This heterogeneity may reflect different cellular density from one nodule to another and the difficulty of estimating the actual weight of the nodule particularly in the presence of partial necrosis or may also reflect different iodide intake (1, 3, 4). The main cause of ATN is a mutation of the TSHr gene conferring constitutive activity of the TSH receptor toward adenylate cyclase (5). More than 30 different mutations have been described, and only a small fraction of the mutants are able to activate constitutively both the cAMP and the inositol phosphate (IP)-diacylglycerol (DAG)-Ca2+ regulatory cascades (6, 7). However, no correlation could be established between the nature of the causal mutation and the phenotype of the tumor. In vitro experiments demonstrated that H2O2 generation is decreased in autonomous adenomas (8). This fits well with the observation that, in humans, only the IP-DAG-Ca2+ cascade stimulates H2O2 generation and that the cAMP cascade down-regulates the production of H2O2 (9). Because H2O2 is a limiting factor for iodide organification (10), our hypothesis was that if H2O2 generation is actually decreased in autonomous nodules in vivo, impaired iodide organification should be observed at least in patients in whom the IP-DAG-Ca2+ cascade is not activated.

The aim of this work was therefore to evaluate, using the iodine perchlorate (I-ClO4) discharge test, iodine organification in subjects with newly diagnosed ATN.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty-six patients with a single ATN, based on the 123I thyroid scan, were included in the study. Patients with necrotic or cystic autonomous nodules (defined as a heterogeneous uptake with low iodide, i.e. 123I, uptake by more than 25% of the total nodule volume) were excluded from the study. Patients with multinodular goiter on thyroid scan were also excluded from the study, as were patients treated or previously treated with antithyroid drugs.

Patients underwent a biological evaluation including serum concentrations of free T3 (FT3), FT4, TSH, thyroid peroxidase (TPO) antibodies, and thyroglobulin (Tg) antibodies and determination of urinary iodine concentrations.

Serum FT4, FT3, TSH, TPO antibodies, and Tg antibodies were measured by electrochemiluminescence (Modular; Roche, Mannheim, Germany). Normal ranges for these hormones were as follows: FT4, 0.8–1.7 ng/dl; FT3, 1.8–4.6 pg/ml; and TSH, 0.4–4 µU/ml. Thyroid and nodule volume was measured by ultrasonography. Institutional review board approval and patient informed consent were obtained before the study.

Perchlorate discharge test

The I-ClO4 discharge test was carried out in all subjects as previously described (11). At time zero, 26 MBq 123I was administered orally with 500 µg stable iodide. Three hours later, a first 10-min scintigraphy was acquired, followed immediately by the administration of an oral solution containing 1 g perchlorate. One hour later, a second 10-min static image was obtained, and a 2-min static image acquisition of a standard containing 13 MBq 123I was also performed. All images were obtained with a Sophy Medical DSX {gamma}-camera (SMV International, Buc, France) equipped with a pinhole collimator with a 205-mm height, 295-mm diameter, and 5-mm aperture.

A distance of 5 cm was maintained between the pinhole collimator and the patient’s neck as well as the standard containing the 123I.

Image analysis

The images were first corrected for the differential pinhole sensitivity in the field of view (12). The ATN boundaries were then manually traced. The total number of counts inside this region of interest (ROI) was recorded from the images obtained before and after the perchlorate discharge test. The counts of the standard were also measured inside a rectangular region of interest placed manually. All of these count values were corrected for radioisotope decay, considering that time zero is the moment of the acquisition of the first thyroid scintigraphy. The 123I discharge, expressed in percent, was then calculated as follows: discharge = [counts before perchlorate – counts after perchlorate)/counts before perchlorate]. The test was considered positive when the discharge from ATN exceeded 15% (11). Additionally, in 37 patients, the uptake of 123I inside the ATN was calculated before and after perchlorate administration from the count number in the ATN ROI, the counts in the standard ROI, and the administered dose.

Statistical analysis

Data are expressed as means ± SD. Differences between groups for normally and nonnormally distributed data were examined by a two-tailed unpaired t test and Mann-Whitney U test, respectively. A {chi}2 test was used for group frequency. Pearson rank correlation coefficient was computed. We considered values of P < 0.05 to indicate statistically significant differences. Statistical analyses were performed using Prism 2 (GraphPad Software, San Diego, CA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Among the 46 subjects with ATN, 31 (67%) were women and 15 (33%) were male (P < 0.001). Female patients were significantly younger than males (48 ± 15 yr. vs. 63 ± 5 yr. (P < 0.001). Eleven patients (24%) were euthyroid, 28 patients (61%) suffered from subclinical hyperthyroidism, and seven patients (15%) were hyperthyroid. In 26 patients (57%), no tracer uptake of surrounding normal thyroid gland was observed. In these cases, the level of TSH was statistically lower than in patients with visible uptake by the normal parenchyma (0.13 ± 0.14 vs. 0.62 ± 0.57 µU/ml, P < 0.001).

A positive discharge test (P+) and a negative discharge test (P–) are illustrated in Fig. 1Go.


Figure 1
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  		FIG. 1. A and B, ATN with a positive response to the perchlorate discharge test, shown before perchlorate (A) and after perchlorate (B) (123I discharge value = 30%); C and D, ATN with a negative response to the perchlorate discharge test, shown before perchlorate (C) and after perchlorate (D) (123I discharge value = 4%).

 
The distribution of the responses to the discharge test shows two very different groups of response without overlap between the groups (Fig. 2Go). Among the 46 ATN, 28 (61%) had a positive discharge test (P+) and 18 (39%) had a negative discharge test (P–) with a mean discharge value of 41.7 ± 13.2% (range, 26.0–77.0%) and 4.5 ± 9.0% (range, –16.0–13.7%), respectively. In the P+ ATN, the discharge was significantly higher than the discharge in their contralateral lobe (3.2 ± 8.4%, P < 0.0001). Only one patient presented a contralateral lobe with positive response to perchlorate test (discharge value = 23.1%). In the P– group, no contralateral lobe presented a positive response to the perchlorate test.


Figure 2
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  		FIG. 2. 123I discharge values comparison between ATN with a positive response (P+) to the perchlorate discharge test and those with a negative response (P–).

 
No difference was found between the P+ and P– groups in terms of serum TPO and Tg antibodies, serum TSH, FT4, or FT3 concentrations, iodide urinary concentrations, or ATN volume (Table 1Go). No difference in proportion of euthyroidism, hyperthyroidism, and subclinical hyperthyroidism or in sex ratio was found between the two groups.


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  		TABLE 1. Clinical characteristic of patients with positive and negative discharge test

 
The ATN volume was significantly correlated with serum FT3 concentrations (r = 0.55; P < 0.001) and TSH level (r = –0.35; P = 0.02) but not with serum FT4 (r = 0.04; P = 0.80).

The 123I uptake in ATN before perchlorate between P+ and P– groups was not different, whereas the difference became significant after perchlorate (Fig. 3Go).


Figure 3
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  		FIG. 3. Comparison between 123I uptake of ATN with a positive response (P+) and those with a negative response (P–) before and after the perchlorate administration (mean ± SD).

 
Interestingly, in the ATN P– group, 123I uptake was significantly correlated with serum FT3 and FT4 concentrations before and after perchlorate but in the ATN P+ group, serum thyroid hormones were not correlated with 123I uptake either before or after perchlorate (Fig. 4Go).


Figure 4
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  		FIG. 4. A, Correlation between 123I uptake after perchlorate administration and FT3 and FT4 serum levels in the P+ group; B, correlation between 123I uptake after perchlorate administration and FT3 and FT4 serum levels in the P– group.

 
Because some patients with normal TSH could not be diagnosed with certainty as having autonomous nodules, we repeated the analysis excluding these patients. The exclusion of these patients did not affect the outcome with the exception of the correlation between serum FT4 and 123I uptake after the perchlorate test in the P– group. This correlation was not significant anymore after exclusion of patients with normal TSH (r = 0.55; P = 0.09). The correlation between serum FT3 and 123I uptake after the perchlorate test in the P– group remained significant after the exclusion of patients with normal TSH (r = 0.72; P = 0.019).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, a positive perchlorate discharge test was observed in 61% of patients with ATN, indicating that iodide organification capability was impaired in more than half of the ATN. In P– patients, serum FT3 and FT4 concentrations were significantly correlated with iodide uptake but not in P+ patients. The correlation between serum FT3 and iodine uptake in P– patients was still significant after the exclusion of patients with normal TSH. This was, however, not the case for serum FT4. The absence of correlation between thyroid hormone levels and iodide uptake in P+ patients suggests that the organification defect observed in ATN affects to a certain extent the production of thyroid hormones. As previously reported, there was a preferential secretion of FT3 by the ATN, and nodule size was strongly correlated with serum FT3 but not with serum FT4 levels (2, 13, 14).

The characteristics of our patients with ATN were similar to those observed in other studies with a higher frequency and lower age at diagnosis in women (2). Only a minority of studied ATN were toxic partly because some patients with toxic nodules were excluded from the study because they were already treated with antithyroid drugs or because it was inappropriate to delay treatment.

Our data fit well with a previous in vitro study showing that increased thyroid hormone synthesis by autonomous nodules is entirely due to an increased iodide transport capacity. In that study, the authors demonstrated that the fractional binding of iodide to protein in autonomous tissue is equal or even sometimes decreased in comparison with the normal surrounding tissue (15). Together, this suggests that iodide organification efficiency is slightly impaired in autonomous nodules. When we measured the uptake of iodide by the surrounding normal tissue, no discharge was observed after perchlorate except for one patient, indicating that the organification impairment affects only the autonomous nodule and not the surrounding normal tissue. It may appear paradoxical that patients with hyperthyroidism present an impaired iodide organification process. Autonomous thyroid nodules are classically responsible for hyperthyroidism; consequently, we did not expect a total organification defect as sometimes observed in congenital hypothyroidism. It is the reason we decided to use the iodine perchlorate discharge test, which is certainly more sensitive to detect a slight impairment in iodide organification than the standard perchlorate test without iodine (16, 17). This test, done with the same dose of iodine, is frequently positive in patients with untreated Graves’ disease (11), a phenomenon attributed either to the concomitant presence of Hashimoto’s thyroiditis or to an inability to organify the increased iodide concentrated by the hyperfunctioning gland. In our study, no relationship was found between iodine organification defect and the level of iodide uptake or the presence of antithyroid antibodies. Iodine contamination may accentuate the degree of hyperthyroidism in patients with autonomous nodules; in addition, iodide excess by saturation of the organification system could give false-positive perchlorate discharge test results. Consequently, patients suspected of iodine contamination based on clinical history and urinary iodine concentrations were excluded from this study.

Therefore, it is doubtful that the observed organification impairment was due to an overload of iodide saturating the normal oxidation system. Consequently, the iodide organification defect may be related to a decreased H2O2 production impairing the efficiency of the oxidation system itself. This explanation may also be valid for the organification impairment observed in Graves’ disease as thyroid-stimulating antibodies are known to decrease H2O2 production in human thyroid (11, 18). In addition, the fact that in ATN the increased iodide intake is associated with a predominance of T3 secretion is compatible with an organification defect. Consequently, in iodine-deficient areas, the preferential secretion of T3 by autonomous nodules may be due not only to the lack of iodine but also to its impaired organification.

The discharge test data distinctly segregate the patients into two groups with regard to organification impairment: those with a negative test (<15%) and those with a positive response who actually reached a discharge value higher than 25%. The clear-cut separation might indicate the existence of two different variants of the disease that we arbitrarily defined as class I for ATN with an organification defect and class II for ATN without this defect. In addition, this bimodal distribution of discharge response suggests that the organification defect results from a monogenic event of unique or diverse origin. Because no genetic analyses were done on the thyroid nodules in this series, we can only speculate about a possible relationship between the mutation that caused the disease and the degree of organification defect. We propose that TSHr mutations acting only on the cAMP cascade could be responsible for ATN with organification defect (class I variant), whereas TSHr mutations or still unknown mutations causing ATN without organification defect (class II variant) would involve both the cAMP and the IP-DAG cascade. The proportion of ATN without organification defect (39%) is higher than the reported proportion of ATN harboring a TSHr mutation able to activate both the cAMP and the IP-DAG-Ca2+ (19). The different clinical characteristics of patients selected in these series may explain this discrepancy. In addition, as acknowledged by the experimenters, functional studies of the various TSHr mutants were performed in transfected COS cells, a situation that may not reflect the activity of the mutant in vivo (20). The limitations of transfection data are illustrated by studies performed on canine TSHr, which activates only the cAMP cascade in vivo but is also able to activate the IP-DAG-Ca2+ cascade when transfected into COS cells (21). The cellular environment may also play a role in the phenotype induced by the mutants because the biological potency of TSHr mutants in thyroid cells does not correlate with cAMP concentrations obtained after transfection into COS cells (22). Therefore, the presence or the absence of an organification defect in ATN is probably not entirely related to the ability of the causal TSHr mutation to activate the IP-DAG-Ca2+ in addition to the cAMP cascade in COS cells.

The present study has one important limitation. We did not measure iodine content of ATN. Consequently, we cannot exclude with certainty that a greater iodine concentration in some ATN could be responsible for a positive discharge test in class I nodules. Nevertheless, there are several arguments against this hypothesis: 1) the absence of discharge in the normal tissue in all except one patient renders unlikely iodine contamination, 2) the two patients with the highest urinary iodine concentrations had a negative discharge test, and 3) iodide uptake was the same in class I and II nodules, suggesting identical iodine content. Last, an unsuspected iodine contamination affecting 61% of a population with normal urinary iodine concentration is highly unlikely.

In conclusion, an iodide organification defect was observed in 61% of a series of 46 ATN. This observation is in accordance with previous in vitro data showing that H2O2 production, the limiting step of iodide organification, is decreased in these nodules. Whether differences in organification capability could predict the risk for evolution to overt hyperthyroidism in patients with ATN remains to be established.


   Footnotes
 
This work was supported by the Fonds National de la Recherche Scientifique Médicale and by the Action de Recherches Concertées de la Communauté Française de Belgique.

Disclosure Statement: All authors have nothing to declare.

First Published Online October 9, 2007

Abbreviations: ATN, Autonomous thyroid nodule; DAG, diacylglycerol; FT3, free T3; IP, inositol phosphate; P+, positive discharge test; P–, negative discharge test; ROI, region of interest; Tg, thyroglobulin; TPO, thyroid peroxidase.

Received April 13, 2007.

Accepted September 28, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Corvilain B, Van Sande J, Dumont JE, Vassart G 2001 Somatic and germline mutations of the TSH receptor and thyroid diseases. Clin Endocrinol (Oxf) 55:143–158[CrossRef][Medline]
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