The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3755-3761
Copyright © 2007 by The Endocrine Society
Update in Thyroidology
E. Chester Ridgway,
Yaron Tomer and
Sandra M. McLachlan
Division of Endocrinology, Metabolism, and Diabetes (E.C.R.), Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045; Division of Endocrinology, Diabetes, and Metabolism (Y.T.), Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45221; and Department of Medicine (S.M.M.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90025
Address all correspondence and requests for reprints to: E. Chester Ridgway, M.D., MACP, University of Colorado Health Science Center, MS 8106, P.O. Box 6511, Aurora, Colorado 80045. E-mail: e.chester.ridgway{at}uchsc.edu.
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Abstract
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The human and mouse genome databases have provided powerful tools to probe many unanswered questions in thyroidology. Mechanistic knowledge regarding thyroid development, thyroid gland regulation by hypothalamic-pituitary function, thyroid hormone transport and action, thyroid autoimmunity and genetics, and thyroid oncogenesis have expanded enormously using molecular genetics. This basic information is providing the foundation for new clinical approaches to the diagnosis and therapy of thyroid disorders. For example, old dogma regarding the transport of thyroid hormones into cells being mediated by passive diffusion is being discarded as knowledge of new small molecule transporters has been discovered and related to human disease. The genetic basis for autoimmune thyroid disease is being unraveled by discovery of genetic variations associated with risk for autoimmune disease and important molecules in the disorder’s pathogenesis. The translation of basic molecular genetic knowledge into clinical care is no better illustrated than in thyroid cancer, in which genetic mutations in molecules of the MAPK pathway have been shown to account for more than 70% of papillary thyroid cancers. Furthermore, certain mutations may predict clinical outcomes, such as cancer recurrence. The new molecular understanding of thyroid cancer causation is now opening a new therapeutic frontier as drugs are developed that modulate the MAPK pathway.
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Introduction
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FROM THE BEGINNING of 2006 to mid-2007, approximately 2000 manuscripts dealing with "thyroid" have appeared in the PubMed database. Thyroid cancer leads the topics with nearly 600 citations; whereas hypothyroidism, hyperthyroidism, and thyroid genetics round out the top four with approximately 350 citations each. The human and mouse genome initiatives have clearly accelerated the pace of new discoveries on the molecular basis of thyroid physiology and pathophysiology. Subclinical thyroid disease continues to attract attention from around the world as investigators sharpen their inquiries into the potential importance of these very common diagnoses.
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Subclinical Hypothyroidism and Cardiovascular Risk
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In September of 2001, a consensus panel concluded that there was no substantial evidence supporting negative outcomes in patients with subclinical hypothyroidism, particularly when the TSH was only minimally elevated between 5 and 10 mU/liter (1). Consequently, the panel could not find compelling data to support treating these patients with levothyroxine. The primary parameters evaluated were symptoms of hypothyroidism, elevated serum levels of cholesterol, cardiac dysfunction, and adverse clinical outcomes. An important conclusion of the panel’s deliberations was the paucity of randomized controlled trials (RCTs) evaluating the efficacy of levothyroxine therapy on any outcome in subclinical hypothyroidism. Since 2001, there has been a gratifying increase in the number of studies that have contributed important new information on the impact of this disorder and the value of treating it (2). The most recent study by Razvi et al. (3) is the largest trial published to date, investigating 100 patients with subclinical hypothyroidism who were recruited from 27 general practice sites in Birmingham, United Kingdom. The patients had a mean TSH of 6.6 mU/liter; they were treated with a fixed dose of 100 µg levothyroxine for 12 wk in a randomized placebo-controlled crossover design. The primary outcomes were serum cholesterol levels and flow-mediated dilatation in the brachial artery. Both parameters were significantly improved by levothyroxine, with serum cholesterol and low-density lipoprotein decreasing by 5.5 and 7.3%, respectively. Also improved after multifactorial analysis were the symptom of "fatigue" (P < 0.006) and the waist-hip ratio (P < 0.001). Laudatory attributes of this study were the recruitment of patients from multiple general practice sites and the utilization of the "crossover" design in the RCT. However, the study was confounded by using patients with a wide distribution of baseline TSH values, thereby limiting the applicability of the conclusions to the specific subgroup of patients with TSH levels between 5 and 10 mU/liter. Additionally, using a fixed dose of levothyroxine of 100 µg/d resulted in approximately 10% of patients being overtreated and having partially suppressed TSH levels. Nonetheless, even eliminating these patients did not change the significance of the effect of levothyroxine on the primary outcomes. These results prompted the authors to speculate that the calculated benefit of levothyroxine therapy in these patients would be a 10% reduction in cardiovascular death over a 10-yr period. However, large RCTs will be necessary to prove or disprove such speculation because recent reviews of observational studies relating cardiovascular morbidity and mortality to subclinical hypothyroidism have not consistently verified such a relationship (4, 5).
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Thyroid Hormone Transport
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One of the intriguing new insights in thyroidology is the discovery that thyroid hormones are actively transported into cells and do not passively diffuse through cell membranes (6). This is mediated by a broad set of different small molecule transporter proteins that are grouped into families, including the organic acid, amino acid, and monocarboxylate transporters (7). Some tissues have a wide array of transporters (for example, the liver), whereas other tissues may have a more limited complement (for example, the brain). This complexity is increased because the different transporters display different specificities for the thyroid hormones. One of the two brain transporters is a sodium-dependent organic acid transporter, OATP1C1, and is specific for T4 and rT3, but excludes T3. The other brain transporter is from the monocarboxylate transporter family, MCT8, and is thyroid hormone specific, transporting T4, T3, and rT3. In 1944, the Allan-Herndon-Dudley syndrome of X-linked mental retardation was first described and involved generalized dystonia, spasticity, and lack of verbal communication along with severe mental retardation (8). Subsequently, these male children were shown to have bizarre thyroid function test abnormalities, including low serum total and free T4, low rT3, elevated total and free T3, and normal or minimally elevated serum TSH levels. Sixty years after the clinical description of this syndrome, its genetic basis was found to be due to mutations or deletion of the MCT8 transporter (9, 10).
In 2006–2007, two independent groups have created transgenic mice lacking MCT8 and shown the same thyroid phenotype that is present in patients with this disorder (11, 12). Surprising to both groups, and as yet unexplained, was the absence of any neurological phenotype in the mice that developed normally and were fertile. Elegant in vivo and in vitro studies in the MCT8 knockout mice showed normal T3 uptake in the liver, elevated T3 content in the liver, and a thyrotoxic gene expression profile in the liver, which included elevated deiodinase 1 activity. Thus, thyroid hormones were entering the liver using alternative transporters. In contrast, brain uptake of T3 was extremely low, and the content of both T3 and T4 was low, but not absent, reflecting the low serum levels of T4 and the conversion of that T4 to T3 in the brain. In contrast to the liver, the brain had a hypothyroid gene expression profile (which was variable because of the many different cell types) and a dramatically elevated deiodinase 2 activity. Central thyroid hormone resistance was documented by T3 infusions when the MCT8 knockout mice were rendered hypothyroid, the serum TSH levels normalizing only with supraphysiological, but not normal, concentrations of serum T3. Thus, the genesis of the bizarre thyroid phenotype in the Allan-Herndon-Dudley syndrome is multifactorial, involving central thyroid hormone resistance driving high thyroid hormone production, a state of hepatic hyperthyroidism contributing to more T3 production, but also T4 consumption via high deiodinase 1 activity. The brain’s inability to transport T3 thereby eliminates one organ that metabolizes T3 and contributes to the high T3 levels. T4 levels are low because of the elevated conversion to T3 in the liver and the increased uptake and conversion to T3 in the brain. Because of these alterations in thyroid hormone transport, an enigmatic paradox of "brain hypothyroidism" coexists with "hepatic thyrotoxicosis."
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Genetics of Thyroid Autoimmunity in Humans
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The past few years have witnessed significant advances in our understanding of the genetic contribution to the etiology of autoimmune thyroid disease (AITD). There is compelling epidemiological evidence for a major genetic influence on the development of AITD (13). The ratios of disease prevalences in siblings of affected individuals vs. the general population is high; moreover, the concordance rate for Graves’ disease and Hashimoto’s thyroiditis is significantly higher in monozygotic twins when compared with dizygotic twins. To date, six genes have been shown to contribute to the development of AITD: CD40, CTLA-4, HLA-DR, protein tyrosine phosphatase-22, thyroglobulin, and TSH receptor (TSHR) (14). In the past year, there has been new mechanistic information on the role of CD40, a member of the TNF-R receptor family of molecules expressed primarily, but not exclusively, on B cells and other antigen-presenting cells (15). CD40 plays a fundamental role in B cell activation, inducing B cell proliferation and antibody secretion (15). Recently, CD40 was identified as a susceptibility gene for Graves’ disease. A C/T single nucleotide polymorphism (SNP) in the 5' untranslated region of the CD40 gene is associated with Graves’ disease with the CC genotype of this SNP conferring risk (16). Further studies demonstrated that the CC genotype increased the translational efficiency of CD40 (17). Because CD40 is highly expressed in B cells and autoreactive B cells are critical for Graves’ disease, it seemed plausible that the C allele increases the risk by increasing CD40 expression in B cells. If this hypothesis is correct, then one might expect this SNP to be associated with other antibody-mediated conditions, because increased CD40 expression on B cells should increase the risk for B cell-mediated autoimmunity in general. However, testing of this CD40 SNP in myasthenia gravis, another antibody-mediated autoimmune disease, showed no association (18). This intriguing finding led to an alternative hypothesis, namely that the C allele enhances CD40 expression in thyroid follicular cells. Indeed, previous studies have shown that CD40 is expressed and functional on thyrocytes (19), and the thyroidal expression of CD40 is up-regulated in Graves’ disease (20). To test this alternative hypothesis, Jacobson and Tomer (14) examined CD40 expression in thyroid tissues (the target tissue in Graves’ disease) and skeletal muscle tissue (the target tissue in myasthenia gravis). The results clearly showed a high level of expression of CD40 in the thyroid with no expression in skeletal muscle, suggesting that the association with Graves’ disease is due to increased CD40 expression on thyroid follicular cells (18). How can increased CD40 expression in the thyroid increase the risk? One can postulate at least two, nonmutually exclusive, potential mechanisms. First, an intrinsic mechanism could be that increased expression of thyrocytes would cause increased T cell activation of CD40 signaling pathway in the thyrocyte, resulting in overexpression of cytokines such as IL-6 thereby inducing thyroid inflammation and autoimmunity. Second, a postulated extrinsic mechanism is based on the observation, made over 20 yr ago, that under certain circumstances thyrocytes can express major histocompatibility complex (MHC) class II molecules and act as antigen-presenting cells (21). Thus, overexpression of CD40 on thyrocytes, driven by the C allele, could enhance the costimulation of T cells by thyrocytes, resulting in the activation of B cells (Fig. 1
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FIG. 1. Possible mechanisms by which genetic alterations in CD40 and CTLA-4 can increase the risk for Graves’ disease. Inheriting the susceptible CC genotype in the 5' untranslated region of the CD40 gene results in increased expression and/or function of CD40 on antigen-presenting cells including thyroid follicular cells and B cells, resulting in activation of both T cells and B cells when combined with other potential susceptibility genes and environmental factors. In contrast, genetic changes in the CTLA-4 gene decrease its expression and/or function, which results in T cell activation and proliferation.
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Genetics of AITD in Animal Models
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Investigating the genetic basis for susceptibility to Graves’ disease is complicated, as for all human disorders, by the heterogeneity of human populations and the impact of environmental factors. Animal models permit studying susceptibility genes in homogenous lines of rodents maintained in pathogen-free facilities to exclude infections, dietary variations and, if appropriate, gender effects. Graves’-like hyperthyroidism arising from antibodies to the TSHR can be induced in some mouse strains by immunization with adenovirus encoding the TSHR (22). Even more effective is immunization with adenovirus encoding the A-subunit of the TSHR (23), the autoantigen responsible for stimulating immune responses that lead to Graves’ disease in humans (24). Mice of the BALB/c strain, unlike B6 mice, immunized with TSHR- or A-subunit adenovirus develop elevated serum T4 levels in association with goiter and thyroid hyperplasia (22, 25). Moreover, hyperthyroidism develops in the offspring of BALB/c x B6 (first filial or F1 generation), suggesting that dominant genes in the BALB/c strain control progression to hyperthyroidism. However, all three mouse strains (BALB/c, B6, and BALB/c x B6) develop TSHR antibodies measured by TSH binding inhibition (TBI), a clinical assay commonly used in Graves’ patients. Recombinant inbred mice have been generated from the F1 progeny of two inbred mouse strains followed by repeated brother x sister matings for more than 20 generations to establish homogenous lines. Individual recombinant inbred lines are renewable, which is an advantage compared with the F2 progeny or backcross populations generated for a particular study. Moreover, high-resolution genetic maps are available for five sets of recombinant inbred strains that share B6 as one of the parental strains (26). One of these sets, the CXB panel, was derived by crossing the hyperthyroid-susceptible BALB/c strain (abbreviation "C") with the resistant B6 strain (abbreviation "B"). Thirteen strains of CXB mice were used to explore genetic factors controlling the development of TSHR antibodies and hyperthyroidism (27). Female mice were characterized before and after three immunizations with A-subunit adenovirus for TSHR antibodies (measured by TBI), serum T4, and thyroid histology. The outcome was as follows: 1) all strains developed TBI activity, albeit at variable levels; 2) six strains became hyperthyroid and one was overtly thyrotoxic; 3) no low TBI responders became hyperthyroid, but high TBI did not predict hyperthyroidism; and 4) preimmunization T4 levels were variable and unrelated to subsequent T4 elevation. Linkage analysis revealed that genes on different chromosomes were involved in the development of TSHR antibodies compared with the development of hyperthyroidism in CXB mice. TBI was associated with two sets of genetic markers on chromosome 17, one of which was in the vicinity of MHC (termed HLA in humans) genes. These findings in CXB mice support a role for MHC in generating TSHR antibodies, consistent with a previous hypothesis that HLA associations in hyperthyroid Graves’ disease or hypothyroidism due to TSHR blocking antibodies reflect the underlying autoimmune process rather than overt clinical disease (28). Unlike the genetic findings for TSHR antibodies, development of hyperthyroidism in CXB mice involved different genetic areas on chromosomes 19 and 10 that are currently being investigated. This study, the first genome scan in murine Graves’ disease, indicates a role for MHC and non-MHC genes in murine Graves’ disease and may provide insight into autoimmune hyperthyroidism in humans. Moreover, the study demonstrates the potential of using recombinant inbred mice for discriminating between "immune-response" and "thyroid-function" susceptibility genes in Graves’ disease.
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Thyroid Cancer and Serum TSH Levels
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When evaluating thyroid nodules for the presence of cancer, most diagnostic strategies emphasize cytological evaluation of fine needle biopsy-derived tissue as the key procedure because other clinical and laboratory data are so nonspecific. Boelaert et al. (29) recently analyzed clinical and laboratory data on 1500 thyroid biopsies performed in Birmingham, United Kingdom. Most of the clinical features that were associated with a positive biopsy for cancer have been previously recognized: male sex (12.2%) was more frequent than female sex (7.4%, P < 0.02); age of less than 30 or greater than 80 yr (P < 0.005); and solitary nodules (10.8%) containing cancer more frequently than diffuse or nodular goiters (4.2%, P < 0.001). A surprising finding was that one laboratory test, the serum TSH level, was also significantly associated with thyroid cancer; the higher the basal TSH level, the more likely the nodule would be positive for cancer. In fact, if the TSH level was above the normal range, the chance of finding cancer approached 30%! Clearly, clinicians who previously assumed that a high TSH in a patient with a nodule indicated a likely diagnosis of AITD, which could safely be treated only with levothyroxine, may need to be even more aggressive with fine-needle aspiration biopsy.
Not only may serum TSH levels aid in the diagnosis of thyroid cancer, but now higher TSH levels have been shown to be importantly associated with both recurrence and mortality. Jonklaas et al. (30) reported follow-up data from the National Thyroid Cancer Treatment Cooperative Study Group, which analyzed 2936 patients from 11 North American institutions; 1548 of the patients had adequate data on serum TSH levels during thyroid hormone therapy for analysis. Their findings clearly show that high-risk patients with stage 3 and 4 disease have fewer recurrences and better survival rates if their TSH levels are suppressed to a level that is undetectable in typical highly sensitive TSH immunoassays. At the same time, low-risk stage 2 patients had significantly better survival rates if the serum TSH levels were only suppressed to below normal, whereas suppression to undetectable was of no added benefit in this group of patients. In low-risk stage 1 patients, no degree of TSH suppression could be shown to significantly improve overall survival, a likely result because so few deaths occurred in this very large subgroup of patients.
A new study from Leiden University in The Netherlands has confirmed these general results. Hovens et al. (31) reported follow-up data on 366 patients treated at a single institution by a uniform treatment protocol. The patients were followed for a mean of 8.9 yr, and all their TSH values were analyzed. The median TSH level had a hazard ratio for death of 2.01 [95% confidence interval (CI), 1.22–3.37] and for recurrence of 1.41 (95% CI, 1.03–1.95). Interestingly, a median TSH of less than 2 mU/liter best predicted relapse-free survival and survival. Because the vast majority of these patients were low risk, this finding is consonant with the findings of Jonklaas et al. (30) in low-risk patients from North America. Taken together, these studies support the recently reported Thyroid Cancer Guidelines (32) from the American Thyroid Association, which recommend aggressive TSH suppression for high-risk thyroid cancer (stages 3 and 4) and more modest TSH suppression in low-risk thyroid cancer (stages 1 and 2).
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Thyroid Cancer and BRAF Mutation
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Understanding the molecular pathogenesis of papillary thyroid cancer began with the discovery that abnormal RET gene activation caused by chromosomal rearrangements was present in a minority of papillary thyroid cancers and resulted in unrestrained and constitutive activity of the MAPK cascade (33). Autophosphorylation of the tyrosine kinase domain of the rearranged RET receptor signals through the RAS-RAF-MEK-MAPK cascade, a fundamentally critical growth-promoting pathway in normal thyroid cells (Fig. 2). In the RAF family, there are three different variants, A-RAF, B-RAF, and C-RAF. B-RAF (hereafter referred to as BRAF) mutations in human cancers were first discovered in 2002 when Davies et al. (34) reported their presence in colorectal carcinoma and melanoma. Although many different mutations in BRAF have been described, more than 90% are the T1799A point mutation, which changes valine to glutamic acid at position 600 in the BRAF protein, resulting in virtually constitutive activation of the MAPK pathway. A major breakthrough occurred with the discovery that BRAF was mutated in approximately 45% of papillary thyroid cancers (35, 36). During the past 2 yr, multiple studies and reviews from around the world have emphasized the importance of the BRAF mutation not only as a novel pathogenetic mechanism, but also for its potential usefulness in prognosis and therapy.
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FIG. 2. Activation of the MAPK pathway in thyroid cancer. RET(RET proto-oncogene) encodes for a receptor tyrosine kinase that is not expressed in normal thyroid cells. Rearranged fusion proteins of RET are found in some papillary thyroid cancers RET/PTC and stimulate RAS activation, which bypasses the need for RET activation by growth factors (GF). Alternatively, mutant RAS (RAS*) can constitutively activate BRAF, whereas mutant BRAF (BRAF*) directly stimulates MEK, which activates ERK, which activates nuclear transcription factors (TF). BRAF can also be activated by fusion of AKAP9 (AKAP/BRAF). [Modified from Ref. 51 with permission.]
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The largest of these studies, a multicenter international study by Xing et al. (37), showed that characteristics of high-risk papillary thyroid cancer, including extrathyroidal invasion, advanced stage of disease, and lymph node metastases were all significantly associated with the BRAF mutation. These findings have been confirmed by other smaller studies from the United States (38), Spain (39), and Korea (40).
In addition, the more aggressive tall cell variant of papillary thyroid cancer seems to harbor the mutation more frequently than the more indolent follicular variant of papillary cancer (38). Furthermore, the BRAF mutation is more frequent in papillary cancers that are larger in size and in patients who are older and of male sex. In contrast, the mutation is infrequently seen in children or those whose cancer was associated with radiation exposure, and it is never seen in pure follicular thyroid cancer. Xing (41) has recently reviewed all published studies and shown that BRAF mutation has an odds ratio of association with extrathyroidal invasion (2.79; 95% CI, 2.21–3.53), lymph node metastases (2.02; 95% CI, 1.65–2.45), and advanced stage 3 and 4 disease (2.05; 95% CI, 1.62–2.59). In general, a cancer that harbors the BRAF mutation is about twice as likely to have these three clinical characteristics. Notwithstanding the power of these associations, it is also clear that cancers without the mutation can also have these poor prognostic features, which emphasizes that other unknown factors also contribute to the determinants of clinical outcomes. Furthermore, not all studies have shown statistically significant associations between the presence of the mutation and these clinical characteristics. For example, in 106 cases of papillary cancer reported by Chung et al. (42) from Korea there was no significant association of the BRAF mutation with age, sex, tumor size, lymph node metastases, extrathyroidal extension, or multifocality of the tumor.
If the BRAF mutation is associated with a more aggressive papillary thyroid cancer phenotype, then it is likely that it is also predictive of higher recurrence and mortality rates. As reviewed by Xing (41), three relatively large studies have shown significantly higher recurrence rates in patients whose cancers are positive for the mutation (37, 39, 43). In the largest of these studies with an average follow-up of 15 months (37), cancer recurrence was associated with the BRAF mutation after extensive multivariant analysis with an odds ratio of 4.0 (95% CI, 1.1–14.1; P = 0.03). Also of particular importance in these studies was the finding that higher recurrence rates were also seen in cancers that were apparently low risk based on demographic and histopathological criteria, when these stage 1 and 2 cancers harbored the mutation. Although it might be assumed that higher recurrence rates are predictive of higher mortality rates, no data have yet shown that BRAF mutation is associated with increased death rates.
These intriguing associations of the BRAF mutation with papillary thyroid cancer have stimulated new and important investigations into molecular pathogenetic mechanisms. For example, loss of radioactive iodine avidity is more common in tumors that contain the mutation (37). At a molecular level, these tumors have also been shown to have lower expression of a number of genes that are directly responsible for iodine uptake and retention. For example, Durante et al. (44) have recently shown decreased expression of the sodium/iodine symporter, the apical iodine transporter, and the thyroglobulin and thyroid peroxidase genes in tumors containing the BRAF mutation compared with those not having the mutation. Subsequent elegant in vitro studies by Liu et al. (45) have shown that inhibition of the MAPK pathway in thyroid cells expressing the BRAF mutation using a MEK-specific inhibitor, U0126, can restore the expression of sodium/iodine symporter, thyroglobulin, thyroid peroxidase, and the TSHR genes. These basic investigations have obvious implications for therapeutic strategies in patients with advanced papillary thyroid cancers that have lost the ability to incorporate therapeutic doses of radioactive iodine. In addition, expression of the BRAF mutation may affect thyroid tumor biology by mechanisms independent of iodine uptake and organification. Specifically, thyroid cells expressing the mutation have decreased expression of some tumor suppressor genes by a process involving hypermethylation, which inhibits gene transcription (46, 47). In contrast, increased expression of genes that promote tumor growth has also been induced in the presence of the BRAF mutation (48, 49). In fact, xenograph in vivo experiments have shown that inhibition of BRAF mutation expression using small interfering RNA technology markedly inhibits tumor growth independent of any effect that this therapy may have on restoring the ability of the tumors to incorporate radioactive iodine (50).
Discovery of the BRAF mutation in papillary thyroid cancer and examining its basic mechanisms of action have raised a whole new list of potential management questions for clinicians. Should BRAF mutation identification become a routine pre- and or postoperative test for patients with suspected thyroid cancer? One might assume that preoperative knowledge that a thyroid tumor contained the mutation would guide physicians toward more aggressive surgery and lymph node dissections. Likewise, postoperative findings of a tumor containing the mutation might result in more liberal use of radioactive iodine with higher initial doses, more frequent follow-up visits looking for recurrence, use of higher doses of suppressive doses of levothyroxine therapy, earlier use of external beam radiation treatments for recurrent disease, and early incorporation of alternative diagnostic modalities such as positron emission tomography-computed tomography and magnetic resonance imaging scanning. However, all of these potential new strategies are not without potential negative consequences and higher costs and should be studied rigorously before adopting any of them. Just as potential new pharmacological agents are emerging and being tested in randomized controlled studies, so should alternative strategies on the management of BRAF mutation positive cases.
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Footnotes
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Abbreviations: AITD, Autoimmune thyroid disease; CI, confidence interval; MHC, major histocompatibility complex; RCT, randomized controlled trial; SNP, single nucleotide polymorphism; TBI, TSH binding inhibition; TSHR, TSH receptor.
Received August 17, 2007.
Accepted August 22, 2007.
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Abstract
Introduction
