Geraldo Medeiros-Neto

Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres

objective  Patients with very large multinodular goitres, frequently found among elderly people, often suffering from cardiovascular or other disabling disorders, may be considered as unsuitable for surgery. We have evaluated the feasibility of relatively high‐dose 131I therapy in such patients. As subclinical or clinical hyperthyroidism is commonly found in these patients, associated with a low radioiodine (RAI) uptake at 24 h, we pretreated a group of patients with a single intramuscular injection of recombinant human TSH (rhTSH 0·45 mg) in order to increase the uptake of the therapeutic dose of RAI.

Iodine Nutrition Improves in Latin America

Iodine deficiency has been a public health problem in most Latin American countries. Massive programs of salt iodization have achieved great progress toward its elimination but no consistent monitoring has been applied. We used the ThyroMobil model to visit 163 sites in 13 countries and assess randomly selected schoolchildren of both genders 6-12 years of age. The median urinary iodine concentration (8208 samples) varied from 72 to 540 microg/L. One national median was below the recommended range of 100-200 microg/L; five were 100-200 microg/L, and seven were higher than 200 microg/L, including three greter than 300 microg/L. Urinary iodine concentration correlated with the iodine content of salt in all countries. Median values of thyroid volume were within the normal range for age in all countries, but the goiter prevalence varied markedly from 3.1% to 25.0% because of scatter. The median iodine content of salt from local markets (2734 samples) varied from 5.9 parts per million (ppm) to 78 ppm and was greater than 15 ppm in 83.1% of all samples. Only seven countries had higher than 15 ppm iodine in 80% of the samples, and only three had greater than 15 ppm in at least 90%. Iodized salt was available at retail level in all countries but its median iodine content was within the recommended range (20-40 ppm) in only five. This study, the first to apply a standardized assessment strategy to recent iodine nutrition in Latin America, documents a remarkable success in the elimination of iodine deficiency by iodized salt in all but 1 of the 13 countries. Some iodine excess occurs, but side effects have not been reported so far, and two countries have already decreased their legal levels of salt iodization and improved the quality control of iodized salt, in part because of our results. The present work should be followed by regular monitoring of iodine nutrition and thyroid function, especially in the countries presently exposed to iodine excess.

Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil.

OBJECTIVE To evaluate the prevalence of chronic autoimmune thyroiditis (CAT) and iodine-induced hypothyroidism, hyperthyroidism (overt and subclinical), and goiter in a population exposed to excessive iodine intake for 5 years (table salt iodine concentrations: 40-100 mg/kg salt). Design This was a population-based, cross-sectional study with 1085 participants randomly selected from a metropolitan area in São Paulo, Brazil, and conducted during the first semester of 2004. METHODS Thyroid ultrasound examination was performed in all participants and samples of urine and blood were collected from each subject. Serum levels of thyroid-stimulating hormone, free thyroxine, and anti-thyroid peroxidase (TPO) antibodies, urinary iodine concentration, thyroid volume, and thyroid echogenicity were evaluated. We also analyzed table salt iodine concentrations. RESULTS At the time the study was conducted, table salt iodine concentrations were within the new official limits (20-60 mg/kg salt). Nevertheless, in 45.6% of the participants, urinary iodine excretion was excessive (above 300 microg/l) and, in 14.1%, it was higher than 400 microg/l. The prevalence of CAT (including atrophic thyroiditis) was 16.9% (183/1085), women were more affected than men (21.5 vs 9.1% respectively, P=0.02). Hypothyroidism was detected in 8.0% (87/1085) of the population with CAT. Hyperthyroidism was diagnosed in 3.3% of the individuals (36/1085) and goiter was identified in 3.1% (34/1085). CONCLUSIONS Five years of excessive iodine intake by the Brazilian population may have increased the prevalence of CAT and hypothyroidism in subjects genetically predisposed to thyroid autoimmune diseases. Appropriate screening for early detection of thyroid dysfunction may be considered during excessive nutritional iodine intake.

MiR-1 Is a Tumor Suppressor in Thyroid Carcinogenesis Targeting CCND2, CXCR4, and SDF-1α

CONTEXT Micro-RNA have emerged as an important class of short endogenous RNA that act as posttranscriptional regulators of gene expression and are constantly deregulated in human cancer. MiR-1 has been found down-regulated in lung, colon, and prostate cancer. OBJECTIVES In this study, we investigated the possible role of miR-1 in thyroid carcinogenesis. DESIGN We have analyzed miR-1 expression in a panel of thyroid neoplasias including benign and malignant lesions and searched for miR-1 targets. RESULTS Our results show that miR-1 expression is drastically down-regulated in thyroid adenomas and carcinomas in comparison with normal thyroid tissue. Interestingly, miR-1 down-regulation was also found in thyroid hyperproliferative nonneoplastic lesions such as goiters. We identified the CCND2, coding for the cyclin D2 (CCND2) protein that favors the G1/S transition, CXCR4, and SDF-1α genes, coding for the receptor for the stromal cell derived factor-1 (SDF-1)/CXCL12 chemokine and its ligand SDF-1/CXCL12, respectively, as miR-1 targets. An inverse correlation was found between miR-1 expression and CXC chemokine receptor 4 (CXCR4) and SDF-1α protein levels in papillary and anaplastic thyroid carcinomas. Consistent with a role of the CCND2 protein in cell proliferation and CXCR4 and SDF-1α proteins in cell invasion and metastasis, functional studies demonstrate that miR-1 is able to inhibit thyroid carcinoma cell proliferation and migration. CONCLUSIONS These results indicate the involvement of miR-1 in thyroid cell proliferation and migration, validating a role of miR-1 down-regulation in thyroid carcinogenesis.

An Outline of Inherited Disorders of the Thyroid Hormone Generating System

To date, various genetic defects impairing the biosynthesis of thyroid hormone have been identified. These congenital heterogeneous disorders result from mutations of genes involved in many steps of thyroid hormone synthesis, storage, secretion, delivery, or utilization. In contrast to thyroid dyshormonogenesis, the elucidation of the underlying etiology of most cases of thyroid dysgenesis is much less understood. It is suggested that genetic factors might play a role in some cases of thyroid dysgenesis and the best candidate genes involved are those encoding transcription factors known to play a role in the embryonic development of the thyroid gland. Moreover, discordance for thyroid dysgenesis is the rule for monozygotic twins as recently reported and this may result from epigenetic phenomena, early somatic mutations, or postzygotic events. In the final part of this review the molecular defects involved in proteins that transport thyroid hormone in the circulation are described: thyroxine-binding globulin (TBG), transtiretin and albumin, that may be associated with altered thyroid function tests and other pathologic conditions such as amyloidotic polyneuropathy.

Relevance of iodine intake as a reputed predisposing factor for thyroid cancer.

UNLABELLED Iodine is a trace element that is essential for the synthesis of thyroid hormone. Both chronic iodine deficiency and iodine excess have been associated with hypertrophy and hyperplasia of follicular cells, attributed to excessive secretion of TSH. This may be associated to thyroid cancer risk, particularly in women. Experimental studies have documented thyroid cancer induction by elevation of endogenous TSH, although in a small number of animals. Iodine deficiency associated with carcinogenic agents and chemical mutagens will result in a higher incidence of thyroid malignancy. Inadequate low iodine intake will result in increased TSH stimulation, increased thyroid cell responsiveness to TSH, increased thyroid cell EGF-induced proliferation, decreased TGFbeta 1 production and increased angiogenesis, all phenomena related to promotion of tumor growth. Epidemiological studies associating iodine intake and thyroid cancer led to controversial and conflicting results. There is no doubt that introduction of universal iodine prophylaxis in population previously in chronic iodine-deficiency leads to a changing pattern of more prevalent papillary thyroid cancer and declining of follicular thyroid cancer. Also anaplastic thyroid cancer is practically not seen after years of iodine supplementation. Iodine excess has also been indicated as a possible nutritional factor in the prevalence of differentiated thyroid cancer in Iceland, Hawaii and, more recently, in China. IN CONCLUSION available evidence from animal experiments, epidemiological studies and iodine prophylaxis has demonstrated a shift towards a rise in papillary carcinoma, but no clear relationship between overall thyroid cancer incidence and iodine intake.

Differential reactivity for galectin-3 in Hürthle cell adenomas and carcinomas

Hürthle cell carcinomas behave as the most aggressive variant of differentiated thyroid carcinoma of follicular origin, with frequent recurrences and higher morbidity. Its differential diagnosis with Hürthle cell adenoma remains a problem for the clinician and for the pathologist. The vertebrate lectins, galectin-1 and galectin-3 have been implicated in the regulation of cellular growth, differentiation, and malignant transformation in thyroid neoplasms. Galectin-3, a β-galactoside binding protein, has been recently found to be highly expressed in papillary and follicular carcinomas. The current study was undertaken to investigate immunohistochemical reactivity for galectin-3 of thyroid specimen tissues with Hürthle cell adenomas (n=14) and carcinomas (n=17), follicular (n=14) and papillary (n=11) carcinomas, colloid goiter (n=30), Hashimoto’s thyroiditis (n=11), follicular adenoma (n=9), and normal thyroid tissues (n=18). Follicular (78.5%) and papillary (82.0%) carcinomas were frequently reactive for galectin-3, more often when some Hürthle cells were present. There was no galectin-3 immunostaining in any of the specimens from Hashimoto’s thyroiditis, colloid goiters or normal thyroid samples, whereas only one case of follicular adenoma was found positive (11.1%). By contrast, galectin-3 immunostaining in Hürthle cell carcinomas was significantly higher (59%) than in Hürthle cell adenomas (7.1%, p<0.05). These results suggest that galectin-3 may potentially serve as a marker in difficult differential diagnosis cases involving Hürthle cell adenomas and Hürthle cell carcinomas.

Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer

Serial weekly serum samples (for 3 weeks) were obtained from 42 patients with differentiated thyroid cancer (DTC, papillary no.=35, follicular no.=6, Hürthle cell no.=1) for serum thyroid hormone, TSH and TG before and after total thyroidectomy. Serum specimens were also obtained one month after radioiodine (131I) therapy followed by suppressive dose of L-thyroxine (L-T4, 2.5 μg/kg). The patients were subdivided into four groups: group I: the DTC was confined to a single solid nodule (no.=12); group II: thyroid malignancy invaded local cervical structures but there were no lymph node metastases (no.=8); group III: DTC with lymph node metastases (no.=6); and group IV: DTC with distant metastases (no.=16). In all group I patients serum TG remained undetectable in spite of elevated serum TSH levels at the 3rd week post-surgery (PS). Only one of group II patients had a detectable serum TG value of 5.2 ng/ml (3rd week PS). By contrast, 37.5% of group III patients had detectable serum TG levels, ranging from 3.4 to 16.8 ng/ml (3rd week PS). Lymph node metastases were detected in 5 of these patients by whole body scan (WBS) and removed surgically in 3. As expected, group IV patients had elevated serum TG values ranging 33.0–958.0 ng/ml and distant metastases were confirmed in all of them by WBS. From the calculations through univariate logistic regression comparing TG concentrations at the 3rd week PS from groups I and II vs groups III and IV, we obtained a cut-off value of 2.3 ng/ml with the following efficacy features: sensitivity= 74.5%; specificity=95%; positive predictive value=92.3%; negative predictive value= 65.5%; and accuracy=73.8%. After 131I and L-T4 suppressive therapy, only 5 out of 36 patients of groups I, II and III had detectable serum TG levels (3.1–7.0 ng/ml) whereas serum TG was detectable in all group IV patients (ranging 2.5–8.6 ng/ml). We concluded that serum TG concentrations above 2.3 ng/ml at the 3rd week PS could be suggestive of lymph node or distant metastases in patients with DTC. Patients with serum TG above this limit could be considered at risk for metastatic disease and higher doses of diagnostic iodine-131 (131I) may be indicated for actinic ablation.

A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect

To screen and subsequently sequence the TPO gene for mutations in patients with congenital goitre, hypothyroidism and evidence for an organification defect (positive perchlorate discharge test).

Congenital Goiter with Hypothyroidism Caused by a 5′ Splice Site Mutation in the Thyroglobulin Gene

In this work we have extended our initial molecular studies of a consanguineous family with two affected goitrous siblings (H.S.N. and Ac.S.N.) with defective thyroglobulin (Tg) synthesis and secretion because of a homozygotic deletion of a fragment of 138 nucleotides (nt) in the central region of the Tg mRNA, identified previously in H.S.N. In order to identify the intron/exon boundaries and to analyze the regions responsible for pre-mRNA processing corresponding to a 138 nt deletion, we performed a screening of a human genomic library. The intron/exon junction sequences were determined from one positive clone by sequencing both strands of the DNA template. The results showed that the deletion mapped between positions 5549 and 5686 of the Tg mRNA and corresponded to exon 30. The positions of the exon limits differed by three nucleotides from the previously reported data obtained from direct sequencing of the deleted reverse transcriptase-polymerase chain reaction fragment from H.S.N. These variations are because the intron/exon junctions in this region were not available at the time when the deletion was first described. The deletion does not affect the reading frame of the resulting mRNA and is potentially fully translatable into a Tg polypeptide chain that is shortened by 46 residues. The same 138 nt deletion was observed in reverse transcriptase-polymerase chain reaction studies performed in the thyroid tissues from Ac.S.N. Genomic DNA analysis showed that a G to T transversion was observed at position +1 in the donor site of intron 30. Both affected patients (H.S.N. and Ac.S.N.) are homozygous for the mutation whereas the normal sister (At.S.N.) had a normal allele pattern. The functional consequences of the deletion are related to structural changes in the protein molecule that either could modify the normal routing of the translation product through the membrane system of the cell or could impair the coupling reaction. Probably the mutant Tg polypeptide might be functionally active in the production of thyroid hormone, because in the presence of a normal iodine ingestion (approximately 150 microg/day), Ac.S.N. was able to maintain normal serum levels of total triiodothyronine (T3) associated with relatively low serum total thyroxine (T4) with normal somatic development without signs of brain damage.