Does Radioactive Iodine Therapy for Hyperthyroidism Cause Cancer?

Radioactive iodine has been considered a safe and effective therapeutic option for hyperthyroidism secondary to Graves disease and autonomously functioning thyroid nodules since the mid-20th century. The question of whether I-131 at the doses used for hyperthyroidism might increase the risk of cancer has been investigated in a number of observational cohort studies over the years, with the preponderance of evidence being reassuring as to its safety. In particular, the 1998 Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFUS) has been widely cited as compelling evidence that I-131 is safe in hyperthyroidism therapy with respect to carcinogenesis. However, in 2019, a study by Kitahara and colleagues re-analyzed the CTTFUS cohort, extending the follow-up time and applying a novel dosimetric model for estimating tissue absorbed doses of radiation. This new analysis concluded that radioactive iodine was associated with an increased risk for mortality from overall cancer, breast cancer, and non-breast solid cancers. Reaction to this study was vociferous and particularly negative in the nuclear medicine literature. This mini-review was inspired by the 2019 CTTFUS controversy, and it is intended to provide the necessary context for clinicians to provide nuanced advice to their patients on the subject. To that end, the pre-2019 literature is surveyed, the 2019 CTTFUS study and a 2020 follow-up are discussed, and lessons from the literature and critical commentaries are considered.

Less is More: Comparing the 2015 and 2009 American Thyroid Association Guidelines for Thyroid Nodules and Cancer.

BACKGROUND: The American Thyroid Association (ATA) has recently revised its guidance pertaining to thyroid nodules and follicular cell-derived thyroid cancer. The 2015 guidelines are massive in both scope and scale, with changes in the organizational approach to risk stratification of nodules and cancer, as well as multiple sections covering new material. This review highlights the major structural and organizational changes, focusing attention on the most dramatically changed recommendations, that is, those recommendations that clinicians will find striking because they call for significant divergence from prior clinical practice. SUMMARY: The revised approach to thyroid nodule risk stratification is based on sonographic pattern, with an emphasis on pattern rather than growth in the long-term surveillance of nodules. Accumulating data have also been incorporated into an updated risk stratification scheme for thyroid cancer that increases the size of the low-risk pool, in part because low-volume lymph nodal metastases are now considered low risk. The most fundamentally altered recommendation is that lobectomy might be considered as the initial surgical approach for follicular cell-derived thyroid cancers from 1 to 4 cm in size. CONCLUSIONS: The underlying theme of the 2015 ATA guidelines is that "less is more." As these new recommendations are adopted, fewer fine-needle aspiration biopsies will need to be done, less extensive surgeries will become more common, less radioactive iodine will be used either for treatment or for diagnostics, and less stimulated thyroglobulin testing will be done. Mastery of these guidelines will help clinicians know when it is reasonable to do less, thus providing responsibly individualized therapy for their patients.

Thyroid Hormone at Near Physiologic Concentrations Acutely Increases Oxygen Consumption and Extracellular Acidification in LH86 Hepatoma Cells.

Thyroid hormone (T3) has been known to regulate the basal metabolic rate for more than a century, but mechanistic understanding is lacking both at the level of the intact organism and in terms of how T3 alters energy expenditure in individual tissues. The current studies investigate the question of which metabolically relevant genes respond acutely as T3 concentrations increase through the physiologic range in liver cells. Because this has been technically unfeasible historically, we developed a modified protocol for extracellular flux analysis using a 96-well Extracellular Flux Analyzer (Seahorse Bioscience). Using a modified extracellular flux protocol and LH86 human hepatoma cells, we established an experimental system where small but significant changes in O2 consumption could be reproducibly quantified as hypothyroid cells were exposed to near-physiologic final concentrations of T3 approximately 2 orders of magnitude lower than most studies (0.04 nM free T3), in only 6-7 hours. Taking advantage of the nondestructive nature of 96-well Extracellular Flux Analyzer measurements, the acute, direct, transcriptional changes that occur were measured in the exact same cells demonstrating increased O2 consumption. An unbiased, genome-wide microarray analysis identified potential candidate genes related to fatty acid oxidation, angiogenesis, nucleotide metabolism, immune signaling, mitochondrial respiration, and cell proliferation. The identified transcriptome is likely enriched in the genes most important for mediating the energetic effects of T3 in hepatoma cells.

All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies.

Metabolic syndrome constitutes a constellation of findings including central obesity, insulin resistance/type 2 diabetes mellitus (DM), dyslipidemia and hypertension. Metabolic syndrome affects 1 in 4 adults in the United States and is rapidly rising in prevalence, largely driven by the dramatic rise in obesity and insulin resistance/DM. Being central to the development of metabolic syndrome and its other related diseases, much focus has been placed on identifying the mitogenic effects of obesity and insulin resistance/DM as mechanistic clues of the link between metabolic syndrome and cancer. Pertinent mechanisms identified include altered lipid signaling, adipokine and inflammatory cytokine effects, and activation of PI3K/Akt/mTOR and RAS/RAF/MAPK/ERK pathways via dysregulated insulin/insulin-like growth factor-1 (IGF-1) signaling. Through variable activation of these multiple pathways, obesity and insulin resistance/DM pre-dispose to hematologic malignancies, imposing the aggressive and chemo-resistant phenotypes typically seen in cancer patients with underlying metabolic syndrome. Growing understanding of these pathways has identified druggable cancer targets, rationalizing the development and testing of agents like PI3K inhibitor idelalisib, mTOR inhibitors everolimus and temsirolimus, and IGF-1 receptor inhibitor linsitinib. It has also led to exploration of obesity and diabetes-directed therapies including statins and oral hypoglycemic for the management of metabolic syndrome-related hematologic neoplasms.

American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models.

BACKGROUND: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. SUMMARY: Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. CONCLUSIONS: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes.

Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice.

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction.

Statins and downstream inhibitors of the isoprenylation pathway increase type 2 iodothyronine deiodinase activity.

The type 2 iodothyronine selenodeiodinase (D2) is a critical determinant of local thyroid signaling, converting T(4) to the active form T(3) at the cytoplasmic face of the endoplasmic reticulum, thus supplying the nucleus with T(3) without immediately affecting circulating thyroid hormone levels. Although inhibitors of the cholesterol synthesis/isoprenylation pathway, such as hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) have been to shown to down-regulate selenoproteins via interruption of normal selenocysteine incorporation, little is known about the effect of statins on D2. Here, we report that statins and prenyl transferase inhibitors actually increase D2 activity in cells with endogenous D2 expression. Although we confirmed that lovastatin (LVS) decreases the activity of transiently expressed D2 in HEK-293 cells, the prenyl transferase inhibitors increase activity in this system as well. LVS treatment increases endogenous Dio2 mRNA in MSTO-211H cells but does not alter transiently expressed Dio2 mRNA in HEK-293 cells. The prenyl transferase inhibitors do not increase Dio2 mRNA in either system, indicating that a posttranscriptional mechanism must exist. Cotreatment with LVS or the prenyl transferase inhibitors with the proteasome inhibitor MG-132 did not lead to additive increases in D2 activity, indirectly implicating the ubiquitin-proteasomal system in the mechanism. Finally, C57BL/6J mice treated with LVS or farnesyl transferase inhibitor-277 for 24 h exhibited increased D2 activity in their brown adipose tissue. These data indicate that statins and downstream inhibitors of the isoprenylation pathway may increase thyroid signaling via stimulation of D2 activity.

Mice lacking Pctp /StarD2 exhibit increased adaptive thermogenesis and enlarged mitochondria in brown adipose tissue.

Pctp(-/-) mice that lack phosphatidylcholine transfer protein (Pctp) exhibit a marked shift toward utilization of fatty acids for oxidative phosphorylation, suggesting that Pctp may regulate the entry of fatty acyl-CoAs into mitochondria. Here, we examined the influence of Pctp expression on the function and structure of brown adipose tissue (BAT), a mitochondrial-rich, oxidative tissue that mediates nonshivering thermogenesis. Consistent with increased thermogenesis, Pctp(-/-) mice exhibited higher core body temperatures than wild-type controls at room temperature. During a 24 h cold challenge, Pctp(-/-) mice defended core body temperature efficiently enough that acute, full activation of BAT thermogenic genes did not occur. Brown adipocytes lacking Pctp harbored enlarged and elongated mitochondria. Consistent with increased fatty acid utilization, brown adipocytes cultured from Pctp(-/-) mice exhibited higher oxygen consumption rates in response to norepinephrine. The absence of Pctp expression during brown adipogenesis in vitro altered the expression of key transcription factors, which could be corrected by adenovirus-mediated overexpression of Pctp early but not late during the differentiation. Collectively, these findings support a key role for Pctp in limiting mitochondrial oxidation of fatty acids and thus regulating adaptive thermogenesis in BAT.

Thyroid hormone-related regulation of gene expression in human fatty liver.

CONTEXT: Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified. OBJECTIVE: The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis. DESIGN: We evaluated gene expression in surgical liver biopsies from 13 obese (nine with type 2 diabetes) and five control subjects using Affymetrix U133A microarrays. PCR validation was performed in liver biopsies using an additional 16 subjects. We also tested thyroid hormone responses in mice fed chow or high-fat diet. SETTING: Recruitment was performed in an academic medical center. PARTICIPANTS: Individuals undergoing elective surgery for obesity or gallstones participated in the study. RESULTS: The top-ranking gene set, down-regulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by T(3) in human skeletal muscle (n = 399; P < 0.001; false discovery rate = 0.07). This gene set included genes related to RNA metabolism (SNRPE, HNRPH3, TIA1, and SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, and PCMT1), and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver after injection of C57BL/6J mice with T(3) (100 microg/100 g body weight); furthermore, T(3)-induced increases in expression of these genes were abolished by high-fat diet. In agreement, expression of these genes inversely correlated with liver fat content in humans. CONCLUSIONS: These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver.

Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation.

BACKGROUND: The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine-needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients. METHODS: A total of 2587 sequential patients were evaluated by thyroid ultrasound and were offered ultrasound-guided FNA (UG-FNA) of all thyroid nodules that measured > or =1 cm during a 10-year period. Results of aspiration cytology were correlated with histologic findings. The prevalence of thyroid cancer in all patients and in those who underwent surgery was determined. Surgical risk was calculated. RESULTS: Tumors that measured > or =1 cm were present in 14% of patients: Forty-three percent of patients had tumors that measured <2 cm in greatest dimension, and 93% had American Joint Committee on Cancer stage I or II disease. The cytologic diagnoses 'positive for malignancy' and 'no malignant cells' were 97% predictive and 99.7% predictive, respectively. Repeat FNA of initial insufficient aspirates, as well as more detailed classification of inconclusive aspirates, improved preoperative assessment of cancer risk and reduced surgical intervention. Fifty-six percent of patients who were referred for surgery because of abnormal cytology had cancer compared with from 10% to 45% of patients historically. An analysis of operative complications from a subset of 296 patients demonstrated a 1% risk of permanent surgical complications. CONCLUSIONS: The current findings demonstrated the benefits of UG-FNA and of a more detailed classification of inconclusive aspirates in the preoperative risk assessment of thyroid nodules, supporting adherence to recently published guidelines.

The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation.

Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase.

Thyroid hormone is a critical mediator of cellular metabolism and differentiation. Precise tissue-specific regulation of the concentration of the active ligand, T(3), is achieved by iodothyronine monodeiodination. Type 3 iodothyronine deiodinase (D3) is the major inactivating pathway, preventing activation of the prohormone T(4) and terminating the action of T(3). Using nontransformed human cells, we show that TGF-beta stimulates transcription of the hDio3 gene via a Smad-dependent pathway. Combinations of Smad2 or Smad3 with Smad4 stimulate hDio3 gene transcription only in cells that express endogenous D3 activity, indicating that Smads are necessary but not sufficient for D3 induction. TGF-beta induces endogenous D3 in diverse human cell types, including fetal and adult fibroblasts from several tissues, hemangioma cells, fetal epithelia, and skeletal muscle myoblasts. Maximum stimulation of D3 by TGF-beta also requires MAPK and is synergistic with phorbol ester and several mitogens known to signal through transmembrane receptor tyrosine kinases but not with estradiol. These data reveal a previously unrecognized interaction between two pluripotent systems, TGF-beta and thyroid hormone, both of which have major roles in the regulation of cell growth and differentiation.

The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate.

WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by Hedgehog signalling in embryonic structures during chicken development. Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop in D2 that confers metabolic instability, whereas the SOCS-box domain mediates its interaction with a ubiquitinating catalytic core complex, modelled as Elongin BC-Cul5-Rbx1 (ECS(WSB-1)). In the developing tibial growth plate, Hedgehog-stimulated D2 ubiquitination via ECS(WSB-1) induces parathyroid hormone-related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECS(WSB-1) mediates a mechanism by which 'systemic' thyroid hormone can effect local control of the Hedgehog-PTHrP negative feedback loop and thus skeletogenesis.

Chronic cardiac-specific thyrotoxicosis increases myocardial beta-adrenergic responsiveness.

Whereas many cardiac symptoms of thyrotoxicosis resemble those of the hyperadrenergic state, circulating catecholamines are reduced or normal in this condition. To test the hypothesis that the thyrotoxic heart is hypersensitive to catechol-amines, we studied beta-adrenergic signaling in a transgenic (TG) mouse in which the human type 2 iodothyronine deiodinase (D2) gene is expressed in myocardium. Because D2 converts T4 to T3, the active form of thyroid hormone, the D2 TG mouse exhibits mild, chronic thyrotoxicosis that is limited to the myocardium. In the current study, we determined that cAMP accumulation in response to either norepinephrine or forskolin treatment was increased in isolated ventricular myocardiocytes and membrane-enriched fractions prepared from these D2 TG hearts as compared with wild type. This increase in adenylyl cyclase (AC) Vmax could not be explained by changes in AC isoform expression or changes in the long or short forms of stimulatory G-protein Gsalpha, which were approximately 10% decreased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC Vmax is mediated by a decrease in the expression of inhibitory G proteins (Gialpha-3 and/or Goalpha). These data suggest that cardiac thyrotoxicosis leads to increased beta-adrenergic responsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.

In vivo dimerization of types 1, 2, and 3 iodothyronine selenodeiodinases.

The goal of the present investigation was to test the hypothesis that types 1, 2, and 3 iodothyronine selenodeiodinases (D1, D2, and D3) can form homodimers. The strategy included transient coexpression of wild-type (wt) deiodinases (target), and FLAG-tagged alanine or cysteine mutants (bait) in human embryonic kidney epithelial cells. SDS-PAGE of the immunoprecipitation pellet of (75)Se-labeled cell lysates using anti-FLAG antibody revealed bands of the correct sizes for the respective wt enzymes, which corresponded to approximately 2-5% of the total deiodinase protein in the cell lysate. Western blot analysis with anti-FLAG antibody of lysates of cells transiently expressing individual FLAG-tagged-cysteine deiodinases revealed specific monomeric bands for each deiodinase and additional minor bands of relative molecular mass (M(r)) of 55,000 for D1, M(r) 62,000 for D2, and M(r) 65,000 for D3, which were eliminated by 100 mM dithiothreitol at 100 C. Anti-FLAG antibody immunodepleted 10% of D1 and 38% of D2 activity from lysates of cells coexpressing inactive FLAG-tagged Ala mutants and the respective wt enzymes (D1 or D2) but failed to immunodeplete wtD3 activity. D1 or D2 activities were present in these respective pellets. We conclude 1) that overexpressed selenodeiodinases can homodimerize probably through disulfide bridges; and 2) at least for D1 and D2, monomeric forms are catalytically active, demonstrating that only one wt monomer partner is required for catalytic activity of these two deiodinases.