Debate and controversy currently surround the recommendations of a recent consensus conference that considered issues related to the management of early, mild, or so-called subclinical hypothyroidism and hyperthyroidism. Intimately related to the controversy is the definition of the normal reference range for TSH. It has become clear that previously accepted reference ranges are no longer valid as a result of both the development of more highly sensitive TSH assays and the appreciation that reference populations previously considered normal were contaminated with individuals with various degrees of thyroid dysfunction that served to increase mean TSH levels for the group. Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter. The remainder with higher values are outliers, most of whom are likely to have underlying Hashimoto thyroiditis or other causes of elevated TSH. Importantly, data indicating that African-Americans with very low incidence of Hashimoto thyroiditis have a mean TSH level of 1.18 mU/liter strongly suggest that this value is the true normal mean for a normal population. Recognition and establishment of a more precise and true normal range for TSH have important implications for both screening and treatment of thyroid disease in general and subclinical thyroid disease in particular.

Background: The optimal management of high-risk patients with differentiated thyroid cancer (DTC) consists of thyroidectomy followed by radioiodine (¹³¹I) therapy. The prescribed activity of ¹³¹I can be determined using two approaches: 1) empiric prescribed activity of ¹³¹I (E-Rx); and 2) dosimetry-based prescribed activity of ¹³¹I (D-Rx). Aim: The aim of the study was to compare the relative treatment efficacy and side effects of D-Rx vs. E-Rx. Methods: A retrospective analysis was performed of patients with distant metastases and/or locoregionally advanced radioiodine-avid DTC who were treated with either D-Rx or E-Rx. Response to treatment was based on RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Results: The study group consisted of 87 patients followed for 51 ± 35 months, of whom 43 were treated with D-Rx and 44 with E-Rx. Multivariate analysis, controlling for age, gender, and status of metastases revealed that the D-Rx group tended to be 70% less likely to progress (odds ratio, 0.29; 95% confidence interval, 0.087–1.02; P = 0.052) and more likely to obtain complete response (CR) compared to the E-Rx group (odds ratio, 8.2; 95% confidence interval, 1.2–53.5; P = 0.029). There was an association in the D-Rx group between the observed CR and percentage of maximum tolerable activity given as a first treatment of ¹³¹I (P = 0.030). The advantage of D-Rx was specifically apparent in the locoregionally advanced group because CR was significantly higher in D-Rx vs. E-Rx in this group of patients (35.7 vs. 3.3%; P = 0.009). The rates of partial response, stable disease, and progression-free survival, as well as the frequency of side effects, were not significantly different between the two groups. Conclusion: Higher efficacy of D-Rx with a similar safety profile compared to E-Rx supports the rationale for employing individually prescribed activity in high-risk patients with DTC.

Background: To effectively treat differentiated thyroid cancer (DTC) with radioiodine (RAI) it is necessary to raise serum thyrotropin (TSH) levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of recombinant human TSH (rhTSH). The aim of our study was to compare the relative efficacy and side effect profile of rhTSH versus THW preparation for RAI therapy of metastatic DTC. Methods: Fifty-six patients (31 women and 25 men) with RAI-avid distant metastases of DTC treated with either rhTSH-aided (n=15) or THW-aided RAI (n=41) and followed for 72±36.2 months were retrospectively analyzed. The groups were comparable in regard to mean size of target lesions (rhTSH vs. THW 6.4 vs. 4.8 cm, p=0.41), mean baseline thyroglobulin level (6995 vs. 5544 ng/mL, p=0.83), distribution of micronodular and macronodular pulmonary metastases (67% vs. 63%, p=0.54, 13% vs. 15% p=0.64, respectively), osseous (53% vs. 29%, p=0.09), brain (0% vs. 2%, p=0.73), and liver/kidney metastases (13% vs. 2%, p=0.61). Patients in the rhTSH group were older (rhTSH vs. THW mean 62 vs. 49 years, p=0.01), and received lower cumulative RAI dose (256 vs. 416 mCi, p=0.03), which was more frequently based on dosimetric calculations (80% vs. 46%, p=0.024). Responses to treatment were based on RECIST 1.1 criteria. Results: Adjusted by age rates of complete response (CR), stable disease (SD), progressive disease (PD), and progression free survival (PFS) were not different between the groups (rhTSH vs. THW CR hazard ratio [HR] 0.97, 95% CI 0.08–11.42, p=0.982; SD HR 3.22, 95% CI 0.79–13.18, p=0.104, PD HR 0.26, 95% CI 0.52–1.26, p=0.094; PFS HR 0.41, 95% CI 0.14–1.23, p=0.112). The only independent risk factor for nonresponding to treatment and presentation with PD was age (HR 1.06, 95% CI 1.02–1.11, p=0.008). Age was also an independent factor affecting PFS (HR 1.04 for each year, 95% CI 1.02–1.07, p=0.001). Rates of leukopenia, thrombocytopenia, xerostomia, and restrictive pulmonary disease after RAI were not significantly different (rhTSH vs. THW 30% vs. 28%, p=0.61, 10% vs. 0%, p=0.37, 0% vs. 12%, p=0.20, 0% vs. 2%, p=0.73, respectively). Conclusions: Patients with metastatic DTC prepared with rhTSH achieve comparable benefit of RAI therapy as those treated after THW.

A multicenter study was undertaken to ascertain prevalence and significance of recombinant human thyrotropin (rhTSH)-stimulated increases in thyroglobulin (Tg) levels in thyroid cancer patients classified to be at low risk for recurrence. Patients were eligible for enrollment if they had undergone near-total or total thyroidectomy and remnant ablation between 1–10 years prior to enrollment and had received thyroxine suppression therapy (THST) with a TSH level of < 0.5 mU/L and Tg level less than or equal to 5 ng/mL within the prior year. Patients with anti-Tg antibodies, distant metastases, or other evidence of residual disease were excluded. Four hundred eighty-six patients were entered into the study, and 300 were considered eligible and comprise the study population. TSH, Tg, and anti-Tg antibody levels were obtained at baseline, followed by intramuscular injection of 0.9 mg of rhTSH on days 1 and 2 and measurement of Tg on day 5. After rhTSH, 53 patients (18%) had elevations in Tg of at least 2 ng/mL, including 33 patients (11%) with increases from baseline of equal to or greater than 5 ng/mL. Patients with an initial advanced stage of disease were more likely to display elevations in Tg after rhTSH. One third of those with stage III disease displayed elevations in Tg of 2 ng/mL or more. Patients within 5 years of thyroidectomy were as likely to display elevations in rhTSH-stimulated Tg as those 5–10 years from surgery. In conclusion, these data suggest rhTSH-stimulated Tg testing without scan may be a useful tool in the follow-up of patients with low-risk thyroid cancer, and may serve to identify patients previously thought free of disease on the basis of undetectable Tg levels while undergoing THST. A strategy is presented for incorporation of this approach into the management of patients with low-risk well-differentiated thyroid cancer.