A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

Insights into the posttranslational structural heterogeneity of thyroglobulin and its role in the development, diagnosis, and management of benign and malignant thyroid diseases

ABSTRACT Thyroglobulin (Tg) is the major glycoprotein produced by the thyroid gland, where it serves as a template for thyroid hormone synthesis and as an intraglandular store of iodine. Measurement of Tg levels in serum is of great practical importance in the follow-up of differentiated thyroid carcinoma (DTC), a setting in which elevated levels after total thyroidectomy are indicative of residual or recurrent disease. The most recent methods for serum Tg measurement are monoclonal antibody-based and are highly sensitive. However, major challenges remain regarding the interpretation of the results obtained with these immunometric methods, particularly in patients with endogenous antithyroglobulin antibodies or in the presence of heterophile antibodies, which may produce falsely low or high Tg values, respectively. The increased prevalence of antithyroglobulin antibodies in patients with DTC, as compared with the general population, raises the very pertinent possibility that tumor Tg may be more immunogenic. This inference makes sense, as the tumor microenvironment (tumor cells plus normal host cells) is characterized by several changes that could induce posttranslational modification of many proteins, including Tg. Attempts to understand the structure of Tg have been made for several decades, but findings have generally been incomplete due to technical hindrances to analysis of such a large protein (660 kDa). This review article will explore the complex structure of Tg and the potential role of its marked heterogeneity in our understanding of normal thyroid biology and neoplastic processes.

Low iodine diet does not improve the efficacy of radioiodine for the treatment of Graves’ disease

Objective Consuming a low-iodine diet (LID) is a widely accepted practice before administering radioiodine (131I) to evaluate and to treat thyroid disease. Although this procedure is well established for the management of patients with differentiated thyroid cancer, its use in patients with benign disease is unclear. So, we aimed to evaluate the influence of a LID on the outcome in patients with Graves’ disease (GD) treated with131I. Subjects and methods We evaluated 67 patients with GD who were divided into 2 groups: one group (n = 31) consumed a LID for 1-2 weeks, and the second group (n = 36) was instructed to maintain a regular diet (RD). Results The LID group experienced a 23% decrease in urinary iodine after 1 week on the diet and a significant 42% decrease after 2 weeks on the diet. The majority (53%) of the patients in the LID group had urinary iodine levels that were consistent with deficient iodine intake. However, there was no difference in the rate of hyperthyroidism’s cure between the LID and the RD groups 6 months after 131I therapy. Furthermore, the therapeutic efficacy did not differ in patients with varying degrees of sufficient iodine intake (corresponding urinary iodine levels: < 10 μg/dL is deficient; 10-29.9 μg/dL is sufficient; and > 30 μg/dL is excessive). Conclusion In the present study, we demonstrated that although a LID decreased urinary iodine levels, those levels corresponding with sufficient or a mild excess in iodine intake did not compromise the therapeutic efficacy of131I for the treatment of GD.