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Small cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with type 2 diabetes mellitus. Using the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort. A total of 5689 patients with treated hypothyroidism and 59 937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v. 125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09–2.20), with the highest risk in the 90–180 days after initiation (adjusted HR 2.30, 95% CI 1.00–5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69–1.36). In this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.

This retrospective study was designed to compare the treatment response of patients with differentiated thyroid cancer (DTC) prepared for radioiodine ablation (RIA) with thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH) stimulation. Patients with DTC were followed‐up retrospectively between 2013 and 2018 in Kaohsiung Chang Gung Memorial Hospital, Taiwan. We compared the excellent response ratios between THW (49.9%) and rhTSH (50.1%) stimulation. Patients were then divided into subgroups, on the basis of age, sex, extrathyroidal extension, lymph node metastasis, and tumor‐node‐metastasis stage, for analysis. In all, 647 patients were followed‐up after RIA. The ratios of THW or rhTSH use in the different subgroups were not statistically significant. In all the patients, the excellent response rate with THW and rhTSH was 80% and 76.5%, respectively, which was not statistically significant. The subgroup analysis, including age, sex, extrathyroidal extension, lymph node metastasis, and tumor‐node‐metastasis stage (low and high risk), showed similar results. Furthermore, the logistic regression analysis revealed no statistically significant differences among the subgroups. The multivariate analysis showed extrathyroidal extension, lymph node metastasis, and high I131 dose were the prognostic factors affecting the excellent response rate. In conclusion, the THW and rhTSH preparations for RIA were similar in terms of the excellent response rates and subgroup clinical outcomes.

In this issue of the Journal, Schlumberger et al. 1 and Mallick et al. 2 describe the administration of radioiodine (iodine-131) after total thyroidectomy in patients with low-risk thyroid cancer. Postsurgical treatment has long played an important role in the management of this increasingly common cancer. 2 In the United States, the incidence nearly tripled (from 2.7 to 7.7 cases per 100,000) from 1973 through 2002. 3 Similar increases have been reported in Europe. 4 Such increases appear to result largely from more frequent radiologic detection and subsequent fine-needle aspiration of small thyroid nodules, leading to the diagnosis of low-risk thyroid cancer. Guidelines of the . . .

To the Editor: The article by Schlumberger et al. (May 3 issue) 1 accurately identifies the lack of evidence for any benefit of radioiodine ablation in patients with low-risk thyroid cancer after complete surgical resection but goes on to compare two radioiodine doses (1.1 GBq and 3.7 GBq) in a randomized fashion. Logically, it would seem to be necessary to establish the benefit of a therapy before investigating its ideal dose. Unfortunately, a systematic review of the literature 2 has shown no definitive benefit for radioiodine ablation in decreasing rates of recurrence or death in patients with low-risk thyroid cancer. Thus, the . . .

Thyroid-stimulating hormone (TSH) receptor antibody (TSH-R-Ab or TRAb) testing plays a pivotal role in arriving at the aetiological diagnosis in patients with thyrotoxicosis. A positive test establishes the diagnosis of Graves’ disease (GD) while a negative result in conjunction with imaging studies supports other possible aetiologies. In patients with GD, TRAb levels at diagnosis and at the time of withdrawal of antithyroid drugs can identify patients who are unlikely to achieve remission and guide clinical management decisions. We provide an algorithm that incorporates TRAb in the decision-making process for the management of thyrotoxicosis. The utility of TRAb in predicting the risk of fetal and neonatal thyroid dysfunction is established and widely accepted in guidelines. TRAb may also help in the diagnosis of Graves’ orbitopathy, especially in euthyroid or hypothyroid patients and its role in guiding its management is evolving as a useful adjunct to the clinical parameters used in making therapeutic decisions.Anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb) indicate thyroid autoimmunity. The most common use of TPOAb is to identify patients at a higher risk of progression to treatment-requiring hypothyroidism. They also aid the diagnosis of immune thyroiditis and Hashimoto’s encephalopathy. Thyroglobulin measurement is used to help guide differentiated thyroid cancer treatment. TgAb is used as an accompanying test with thyroglobulin measurement as its presence can interfere with the thyroglobulin assay. A negative TgAb result reduces the likelihood of, but does not exclude, interference with thyroglobulin assay.

This trial compared two thyrotropin-stimulation methods and two 131I doses for postoperative ablation in patients with low-risk thyroid cancer. Rates of ablation were similar in all treatment groups. Doses lower than those currently recommended may be adequate for this condition. Radioiodine ( 131 i) is administered to patients with thyroid cancer after total thyroidectomy for three reasons 1 – 3 : first, to eradicate normal-thyroid remnants (ablation) in order to achieve an undetectable serum thyroglobulin level; second, to irradiate any neoplastic focus in order to decrease the risk of recurrence; and third, to perform 131 I total-body scanning for persistent carcinoma. Successful ablation is defined by the combination of undetectable serum thyroglobulin levels after thyrotropin stimulation and normal results on neck ultrasonography 6 to 12 months after 131 I administration. 2 , 3 When these criteria are met, approximately 1% of patients have a recurrence. 4 – 6 In . . .

Abstract Context Scarce data exist regarding the relevance of stimulatory (TSAb) and blocking (TBAb) thyrotropin receptor antibodies in the management of Graves disease (GD). Objective To evaluate the clinical utility and predictive value of TSAb/TBAb. Design Prospective 2-year trial. Setting Academic tertiary referral center. Patients One hundred consecutive, untreated, hyperthyroid GD patients. Methods TSAb was reported as percentage of specimen-to-reference ratio (SRR) (cutoff SRR < 140%). Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine thyrotropin (TSH, thyroid stimulating hormone) alone (cutoff > 40% inhibition). Main Outcome Measures Response versus nonresponse to a 24-week methimazole (MMI) treatment defined as biochemical euthyroidism versus persistent hyperthyroidism at week 24 and/or relapse at weeks 36, 48, and 96. Results Forty-four patients responded to MMI, of whom 43% had Graves orbitopathy (GO), while 56 were nonresponders (66% with GO; P < 0.01). At baseline, undiluted serum TSAb but not thyroid binding inhibitory immunoglobulins (TBII) differentiated between thyroidal GD-only versus GD + GO (P < 0.001). Furthermore, at baseline, responders demonstrated marked differences in diluted TSAb titers compared with nonresponders (P < 0.001). During treatment, serum TSAb levels decreased markedly in responders (P < 0.001) but increased in nonresponders (P < 0.01). In contrast, TBII strongly decreased in nonresponders (P = 0.002). All nonresponders and/or those who relapsed during 72-week follow-up period were TSAb-positive at week 24. A shift from TSAb to TBAb was noted in 8 patients during treatment and/or follow-up and led to remission. Conclusions Serum TSAb levels mirror severity of GD. Their increase during MMI treatment is a marker for ongoing disease activity. TSAb dilution analysis had additional predictive value.

Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only.

This letter provides quality-of-life results from the authors' article in a form that is consistent with the concomitantly published results of another trial. The two studies have consistent results, not only in terms of ablation success rates but also quality-of-life scores. To the Editor: Last year, we 1 and Schlumberger et al. 2 (May 3 issue) reported that low-dose radioiodine ablation was as effective as higher-dose radiation for the management of differentiated thyroid cancer. We also reported that ablation success was not influenced by the use of recombinant human thyrotropin (thyrotropin alfa) just before ablation, as compared with the use of thyroid hormone withdrawal. These data suggest that patients can now be treated with the use of low-dose radioiodine (1.1 GBq) and thyrotropin alfa. Both articles provided quality-of-life assessments. 1 , 2 In the Supplementary Appendix that appears with the full text of our article at NEJM.org, . . .

Abstract Context Levothyroxine is one of the most prescribed medications in the United States. Objective This study explores the appropriateness of levothyroxine prescriptions. Methods A retrospective multicenter study was conducted on adult patients who were prescribed levothyroxine for the first time between 2017 and 2020 at three academic centers in the United States. We classified each case of levothyroxine initiation into one of three mutually exclusive categories: appropriate (clinically supported), indeterminate (clinically unclear), or nonevidence based (NEB, not clinically supported). Results A total of 977 participants were included. The mean age was 55 years (SD 19), there was female (69%) and White race predominance (84%), and 44% had possible hypothyroid symptoms. Nearly half of the levothyroxine prescriptions were considered NEB (528, 54%), followed by appropriate (307, 31%) and indeterminate (118, 12%). The most common reason for NEB prescription was an index thyrotropin (TSH) value of less than 10 mIU/L without previous TSH or thyroxine values (131/528, 25%), for appropriate prescription, was overt hypothyroidism (163/307, 53%), and for an indeterminate prescription was a nonconfirmed subclinical hypothyroidism with TSH greater than or equal to 10 mIU/L (no confirmatory testing) (51/118, 43%). In multivariable analysis, being female (odds ratio [OR]: 1.3; 95% CI, 1.0-1.7) and prescription by a primary care provider (OR: 1.5; 95% CI, 1.2-2.0) were associated with NEB prescriptions. Conclusion There is a considerable proportion of NEB levothyroxine prescriptions. These results call for additional research to replicate these findings and to explore the perspective of those prescribing and receiving levothyroxine.