J. A. Franklyn

Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer

BACKGROUNDnIt is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal.nnnMETHODSnAt 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay.nnnRESULTSnA total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11).nnnCONCLUSIONSnLow-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

The management of hyperthyroidism

Although effective treatments for hyperthyroidism are available, none is perfect. Particularly with respect to Graves disease, what is needed is a therapy directed at modulating the disease process itself rather than merely reducing the synthesis and secretion of thyroid hormones in the hope that the underlying Graves disease will remit. Greater understanding of the pathogenesis of Graves disease, resulting from cloning of the thyrotropin receptor and better knowledge of the interactions between these receptors or other thyroid antigens and the immune system, may lead to such treatment. Broad-spectrum immunosuppression, with all its side effects, is not the answer; more focused therapies to inhibit the immune response to specific thyroid antigens may represent the treatment of the future. Meanwhile, radioiodine therapy is the most effective and convenient method of achieving long-term control of hyperthyroidism, although at the cost of hypothyroidism in many patients.

Mortality after the Treatment of Hyperthyroidism with Radioactive Iodine

BACKGROUNDnHyperthyroidism affects many organ systems, but the effects are usually considered reversible. The long-term effects of hyperthyroidism on mortality are not known.nnnMETHODSnWe conducted a population-based study of mortality in a cohort of 7209 subjects with hyperthyroidism who were treated with radioactive iodine in Birmingham, United Kingdom, between 1950 and 1989. The vital status of the subjects was determined on March 1, 1996, and causes of death were ascertained for those who had died. The data on the causes of death were compared with data on age-specific mortality in England and Wales. The standardized mortality ratio was used as a measure of relative risk, and the effect of covariates on mortality was assessed by regression analysis.nnnRESULTSnDuring 105,028 person-years of follow-up, 3611 subjects died; the expected number of deaths was 3186 (standardized mortality ratio, 1.1; 95 percent confidence interval, 1.1 to 1.2; P<0.001). The risk was increased for deaths due to thyroid disease (106 excess deaths; standardized mortality ratio, 24.8; 95 percent confidence interval, 20.4 to 29.9), cardiovascular disease (240 excess deaths; standardized mortality ratio, 1.2; 95 percent confidence interval, 1.2 to 1.3), and cerebrovascular disease (159 excess deaths; standardized mortality ratio, 1.4; 95 percent confidence interval, 1.2 to 1.5), as well as fracture of the femur (26 excess deaths; standardized mortality ratio, 2.9; 95 percent confidence interval, 2.0 to 3.9). The excess mortality was most evident in the first year after radioiodine therapy and declined thereafter.nnnCONCLUSIONSnAmong patients with hyperthyroidism treated with radioiodine, mortality from all causes and mortality due to cardiovascular and cerebrovascular disease and fracture are increased.

Circulating lipids and minor abnormalities of thyroid function

OBJECTIVE We determined the effect of subclinical hyperthyroidism (defined as low circulating TSH with normal serum free T4) and subclinical hypothyroidism (raised serum TSH with normal free T4) on fasting levels of blood lipids.

Thyroxine replacement therapy and circulating lipid concentrations

OBJECTIVE Hypothyroidism is a common disorder and while the association of overt hypothyroidism with hyper‐cholesterolaemia is clear, the effect upon lipids of the minor abnormalities of thyroid function often found in those receiving T4 replacement therapy is unclear. The aim of the present studies was to define in those with hypothyroidism the effect upon circulating lipids of subtle changes in thyroid status, indicated by serum TSH values below or above the normal range.

Relation between serum interleukin‐6 and thyroid hormone concentrations in 270 hospital in‐patients with non‐thyroidal illness

OBJECTIVESu2003Non‐thyroidal illness (NTI) is frequently accompanied by alterations in circulating thyroid hormone concentrations, despite patients remaining clinically euthyroid. The mechanisms accounting for these changes in circulating thyroid hormone concentrations remain unknown. Much attention has focussed on the role of inflammatory cytokines which are known to be important mediators of disease. The aim of this study was to investigate the role of the cytokine interleukin‐6 (IL‐6) in alterations of thyroid hormone metabolism seen in NTI.

Weight gain following treatment of hyperthyroidism.

OBJECTIVE Patients frequently express concern that treating hyperthyroidism will lead to excessive weight gain. This study aimed to determine the extent of, and risk factors for, weight gain in an unselected group of hyperthyroid patients.

No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies.

The cytotoxic T lymphocyte associated‐4 (CTLA‐4) gene is a candidate for T‐cell mediated autoimmune disease and polymorphism has been reported to be associated with both type 1 diabetes and autoimmune thyroid disease. A previously unreported polymorphism of the promoter region of the human CTLA‐4 gene has recently been described in a sample of a normal control population. We investigated the distribution of this polymorphism, situated at position ‐318 to the ATG start codon and resulting in a C–T change leading to an Mse I restriction site, in both population based case control studies and family studies in patients with Graves disease (Caucasian and Hong Kong Chinese), autoimmune hypothyroidism and systemic lupus erythematosus (SLE).

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours.

objective Thyroid hormones (THs) perform essential roles in pituitary function. They regulate anterior pituitary hormone secretion and are also key determinants of pituitary cell proliferation and differentiation. The critical role of deiodinase enzymes, which serve as prereceptor regulators of TH action, remains largely unexplored. Three deiodinase enzymes metabolize active and inactive THs and thereby determine tissue concentrations of the biologically active ligand, tri‐iodothyronine (T3). We hypothesized that aberrant expression of deiodinase enzymes and/or altered enzyme activity in pituitary tumours may change tissue concentrations of THs and influence their growth and secretory characteristics.

PTTG and PBF repress the human sodium iodide symporter.

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this ∼1u2009kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.