Value of thyroglobulin to 131I uptake ratio in selection of initial therapy dose of 131I in patients with differentiated thyroid carcinoma.

AIM: To test the hypothesis that the ratio of thyroglobulin (Tg) to 131I uptake in the thyroid bed during the immediate post-thyroidectomy work-up could be used before first 131I treatment to detect patients with residual or metastatic thyroid cancer and justify the administration of a higher ablation dose in selected cases and a possibly better therapeutic effect. METHODS: We retrospectively studied 293 patients with differentiated thyroid carcinoma that received their first 131I treatment in our department. Patients with Tg >100 ng/mL, 131I uptake >10% and measurable Tg-specific autoantibodies, were excluded. According to the post-therapy total body scan (TBS), we divided them in 2 groups: group I, without metastases (negative TBS), and group II, with metastases (positive TBS). The ratio of Tg to 131I uptake measured before the first 131I treatment was calculated in both groups. RESULTS: A total of 248 patients were included in the study; 225 in group I and 23 in group II. Tg to 131I uptake ratio was significantly lower in group I (mean 2.17 ng/mL/%, range 0-36), than in group II (mean 32.7 ng/mL/%, range 2.14-220), (P<0.01). The sensitivity, specificity and accuracy (using a threshold ratio 7 ng/mL/% as normal) were all 95.6% for predicting a positive post-therapy TBS. CONCLUSIONS: The use of a threshold ratio 7 ng/mL/% as the upper limit of normal provides useful information with higher sensitivity and specificity in identifying patients with metastatic disease creating the possibility for the selective use of higher initial iodine therapy doses.

Recombinant human thyrotropin in the management of thyroid cancer.

Radioiodine has been shown to reduce recurrences and improve survival in well-differentiated thyroid cancer. To maximize the effectiveness of radioiodine therapy, patients are first treated by total thyroidectomy and then allowed to become hypothyroid. The elevation of thyroid-stimulating hormone, or thyrotropin (TSH), that occurs with hypothyroidism stimulates uptake of radioiodine in normal and cancerous thyroid tissues. A recent advance has been the introduction of recombinant human TSH (rhTSH), which is administered intramuscularly prior to testing with radioiodine. Phase III trials have demonstrated that rhTSH stimulates both uptake in and production of thyroglobulin by thyroid cells and the results are comparable to those of hypothyroid protocols in the majority of patients. Patients prefer the rhTSH protocol because they continue to ingest exogenous thyroid hormone and the symptoms of hypothyroidism are avoided. The rhTSH protocol is preferable in patients with pituitary dysfunction and in those who cannot tolerate hypothyroidism. RhTSH can also allow treatment of patients who have not had an adequate thyroidectomy and who are poor candidates for reoperation.

Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study).

Current diagnostic studies [radioiodine uptake and serum thyroglobulin (Tg) levels] for residual or metastatic thyroid tissue in patients with differentiated thyroid carcinoma require a hypothyroid status necessary for adequate endogenous TSH stimulation. However, almost all patients have symptoms of clinical hypothyroidism during this period. As shown in the present study, recombinant human TSH (rhTSH) allows stimulation of 131I uptake and Tg release from residual thyroid tissue in euthyroid patients. To assess safety, dosage, and preliminary efficacy, comparison was made of the stimulation of 131I uptake and Tg release after rhTSH administration and after T3 withdrawal in 19 patients after a recent thyroidectomy for differentiated thyroid carcinoma. Various doses (10-40 U) of rhTSH were injected im for 1-3 days in patients receiving suppressive doses of T3. Twenty-four hours after the last dose of rhTSH, 1-2 mCi 131I were administered, followed by a neck and whole body scan 48 h later. After discontinuing T3 for a median period of 19 days (range, 15-28), endogenous serum TSH levels were markedly elevated, and the patients were given a second dose of 131I and rescanned 48 h later. The injections of rhTSH were tolerated well. No major adverse effects were reported; nausea was reported in 3 (16%) and vomiting in 1 of the patients treated with high doses. The quality of life, as measured by two psychometric scales, was far better during rhTSH treatment than after T3 withdrawal. The peak levels of serum TSH (mean +/- SD) after a single dose of 10, 20, or 30 U were 127 +/- 19, 309 +/- 156, and 510 +/- 156 mU/L, respectively, and occurred 2-8 h after injection. Twenty-four hours after the injection, TSH levels decreased to 83 +/- 31, 173 +/- 73, and 463 +/- 148 mU/L in these treatment groups, respectively. The quality of the thyroid scans and the number of sites of abnormal 131I uptake were similar after rhTSH treatment and in the hypothyroid scans in 12 (63%) patients. Two additional sites of uptake in the chest and one in the thyroid bed, not visible on the hypothyroid scans, were identified in 3 (16%) patients after rhTSH. In 1 patient a focus of uptake was better visualized after rhTSH than after withdrawal. In 3 (16%) other patients, 1 lesion in the chest and 2 in the neck were seen only after T3 withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)

Thyroglobulin molecules internalized by thyrocytes are sorted in early endosomes and partially recycled back to the follicular lumen.

Thyroglobulin (Tg) molecules stored in thyroid follicle lumens are heterogeneous in terms of iodine and hormone contents. It has been suggested that thyroid hormone is preferentially produced from the most highly iodinated Tg molecules and that thyrocytes are capable of selecting these molecules. The cellular localization as well as the molecular basis of such a selection process are not known. The present work was undertaken to determine whether there is selectivity at the step of endocytosis and, if not, to discover other possible mechanisms. Studies were conducted on reconstituted thyroid follicles (RTF) in culture. We compared the ability of thyrocytes to internalize Tg and an exogenous protein, BSA, which is neither iodinated nor glycosylated. To identify the protein, Tg and BSA were coupled to gold particles of different size and microinjected in a fixed ratio into the lumen of RTF. Neither of the two protein gold probes detected by transmission electron microscope bound at the cell surface, and both entered the cells at a similar rate and were concentrated in early endosomes. After 20 min, both Tg-G and BSA-G were segregated into distinct vacuolar structures. At 60 min, the intracellular content of BSA-G (mainly in prelysosomes and lysosomes) was 2- to 3-fold higher than that of Tg-G. At the same time, there was a marked reduction in the BSA-G/Tg-G ratio in the lumen. The differences between the Tg-G and BSA-G distribution patterns that were amplified in TSH-treated RTF are in keeping with a back-transfer of internalized Tg toward the lumen. The existence of a cell to lumen transport of previously endocytosed Tg was further documented using intralumenal [125I]Tg as a marker. RTF pulse labeled with tracer amounts of [125I]iodide were shortly incubated with TSH to induce [125I]Tg endocytosis, and the fate of internalized [125I] Tg was studied in a chase incubation period of up to 4 h. At 20 C, where the degradation of internalized Tg is blocked, we observed a time-dependent decrease in intracellular [125I]Tg and a corresponding increase in the lumenal [125I]Tg content. This cell to lumen [125I]Tg transfer was inhibited by primaquine. In conclusion, our data show that 1) the thyroid apical endocytic process does not exhibit selectivity for Tg; 2) the thyrocyte possesses a sorting machinery for endocytosed ligands; and 3) internalized Tg molecules can be recycled back to the follicular lumen.(ABSTRACT TRUNCATED AT 400 WORDS)

Resistance to experimental autoimmune thyroiditis is correlated with the duration of raised thyroglobulin levels.

We have used the mouse model of experimental autoimmune thyroiditis (EAT) to examine the hypothesis that the strengthening of self-tolerance to thyroglobulin by exogenous mouse thyroglobulin (MTg) or stimulation of endogenous MTg secretion by thyroid-stimulating hormone (TSH) is correlated with the length of time MTg rises above the normal range. Bacterial lipopolysaccharide (LPS) treatment increases the initial half-life of MTg from about 3 hr to about 5 hr, probably interfering with its clearance by the mononuclear phagocytic (reticuloendothelial) system. By pretreating mice with LPS, a subtolerogenic MTg dose is rendered tolerogenic. Similarly the effect of TSH infusion by osmotic minipumps, which stimulates MTg secretion and also strengthens tolerance to MTg, can be enhanced by injecting LPS shortly after pump implantation. The resulting increase in MTg level (due to delayed clearance of MTg) is greater than that from TSH alone and suppresses further the animals' susceptibility to disease induction by MTg and adjuvant. Moreover, resistance following pretreatment with LPS and subtolerogenic MTg is mediated by CD4+ suppressor T cells, as shown recently for the suppression in mice given high doses of tolerogenic MTg. These experiments are in full agreement with the hypothesis and confirm that small increases in circulating MTg concentrations, which could occur physiologically, can be effective in protecting against EAT induction.