Meyer Knobel

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.

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.

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.

Thyroperoxidase Gene Mutations in Congenital Goitrous Hypothyroidism with Total and Partial Iodide Organification Defect

Mutations of the thyroperoxidase (TPO) gene have been reported as being the most severe and frequent abnormality in thyroid iodide organification defect (IOD) causing goitrous congenital hypothyroidism. The objective of this study was to screen and subsequently identify TPO gene mutations in patients with congenital hypothyroidism with evidence of total iodine organification defects (TIOD) or partial iodine organification defect (PIOD) as defined by the perchlorate discharge test. Seven goitrous patients with TIOD and seven patients with PIOD, from three and five unrelated families, respectively, were studied. We were able to detect different TPO genes mutations in patients with TIOD and PIOD. In TIOD families the results were as follows: (1) a homozygous GGCC insertion at exon 8, position 1277 (family 1); (2) compound heterozygosity with a GGCC insertion at exon 8 (1277) and a nucleotide substitution in exon 11 (2068G>C) (family 2); (3) compound heterozygosity with the mutation 2068G>C in exon 11 and a C insertion in exon 14 between positions 2505-2511 (family 3). In patients with PIOD we have detected: (1) only one heterozygous mutation in two families (4 and 5), in exons 11 and 10 (2084G>A and 1780C>A); (2) a compound heterozygous condition in one family (family 6), with mutations, respectively in exons 8 and 10 (1242G>T and 1780C>A); (3) only polymorphisms (family VII) and (4) a heterozygous mutation in the first base of the border exon/intron 9 +1G>T (family VIII). We did not detect inactivating mutations in exons 11, 16, and 21 of the THOX2 gene where mutations have been previously described. We concluded that homozygous and compound heterozygous mutations found in TIOD characterized the autosomal recessive mode of inheritance and will translate a nonfunctional protein or a protein that may not reach the apical membrane. As for PIOD, the majority of the studied kindreds had only heterozygous mutations and/or polymorphisms. It is conceivable that these TPO gene sequence alterations may partially affect the functional state of the translated protein or affect its transport to the apical membrane.

Natural course of iodine-induced thyrotoxicosis (Jodbasedow) in endemic goiter area: A 5 year follow-up

In the Balsas region of North Brazil (85% prevalence of goiter), 1876 goitrous subjects (1663 with goiter grade I and II and 103 with grade III multinodular goiter) were treated with 1 ml of iodized oil im (I-oil). From the population with grade III goiter we were able to follow-up for 5 yr 13 euthyroid goitrous patients (group 1 ) and 8 goitrous individuals (group 2) who developed iodine-induced thyrotoxicosis (NT, 0.42% of the total population or 7.76% of the multinodular goiter subjects). The two groups were matched for age and goiter size, and had no significant differences in the baseline levels of thyroid hormone concentration, T3/T4 ratio or mean serum TSH. However, group 2 had a higher concentration of serum Tg, and 48 h after challenge with 10 U of bovine TSH (bTSH) had a significantly higher absolute release of T3 and Tg than group 1. In 4 patients IIT was transitory and resolved by 12 months. Four other subjects, however, maintained a mild clinical form of IIT that only normalized at 50 months. Only one patient needed treatment with methylmercaptoimidazol. There was no evidence of autoantibodies (TSH-receptor inhibiting antibody, anti-Tg or anti-microsomal antibodies) against thyroid antigens in group 2 patients. All subjects, including those with thyrotoxicosis, showed a remarkable shrinkage of the goiter by 60 months which was reflected by a significantly lower absolute response of T3 and Tg after bTSH. We conclude that IIT induced by I-oil is a rare complication of I-oil prophylaxis in a general goitrous population, is more common in patients with multinodular goiters and has a transient form and a persistent form that tends to resolve spontaneously by 60 months.

Prevalence of chronic autoimmune thyroiditis in the urban area neighboring a petrochemical complex and a control area in Sao Paulo, Brazil

PURPOSE To evaluate the prevalence of chronic autoimmune thyroiditis in 2 urban areas of metropolitan São Paulo (Brazil): Polo Area neighboring a large petrochemical complex and São Bernardo Campo Area (control area). SUBJECTS AND METHODS Subjects were randomly included from the adult population (20 to 70 years of age) of both genders (women 80%, men 20%) who voluntarily agreed to participate. From the Polo Area, in the vicinity of a large petrochemical industrial complex, 409 subjects were included; from the control area (São Bernardo Campo Area) 420 individuals were included. All subjects were clinically examined, and a detailed record of past thyroid illness and medications was obtained. Ultrasonographic studies were performed using a portable GE Medical Systems apparatus. Blood samples were obtained for free T4, serum TSH, and serum anti-thyroid peroxidase autoantibodies. Urine specimens were collected in Monovette syringes for assaying iodine content. Salt samples were collected at households, and the iodine content was measured. RESULTS Chronic autoimmune thyroiditis was diagnosed both echographically (marked hypoechogenicity) and immunologically (presence of autoantibodies against thyroid peroxidase). In the Polo Area, 15.6% of the examined population had chronic autoimmune thyroiditis, and in the control area (São Bernardo Campo Area), 19.5% of the population had evidence of chronic autoimmune thyroiditis (P > 0.057, not significant). The prevalence of hypothyroidism was 4.9% in the Polo Area and 8.3% in the São Bernardo Campo Area (P = 0.0461 significant). Taking the 2 populations together, 6.6% had hypothyroidism (about one third of these patients were on L-T4 treatment). The mean thyroid volume was 11.2 mL. Domestic salt had a normal concentration of iodine (35.5 + 6.61 mg/kg). Urinary excretion of iodine was above 300 microg Iodine/L in 58.5% of the total population. CONCLUSION The high iodine intake (above 300 microg Iodine/L of urine) that was present from 1998 through 2005 may be related to a higher prevalence of chronic autoimmune thyroiditis in both areas that were studied. There was no apparent or documented relationship of chronic autoimmune thyroiditis prevalence to the proximity to the petrochemical complex.

Association of Low Sodium-Iodide Symporter Messenger Ribonucleic Acid Expression in Malignant Thyroid Nodules with Increased Intracellular Protein Staining

CONTEXT The expression of sodium iodide symporter (NIS) is required for iodide uptake in thyroid cells. Benign and malignant thyroid tumors have low iodide uptake. However, previous studies by RT-PCR or immunohistochemistry have shown divergent results of NIS expression in these nodules. OBJECTIVE The objective of the study was to investigate NIS mRNA transcript levels, compare with NIS and TSH receptor proteins expression, and localize the NIS protein in thyroid nodules samples and their surrounding nonnodular tissues (controls). DESIGN NIS mRNA levels, quantified by real-time RT-PCR, and NIS and TSH receptor proteins, evaluated by immunohistochemistry, were examined in surgical specimens of 12 benign and 13 malignant nodules and control samples. RESULTS When compared with controls, 83.3% of the benign and 100% of the malignant nodules had significantly lower NIS gene expression. Conversely, 66.7% of the benign and 100% of malignant nodules had stronger intracellular NIS immunostaining than controls. Low gene expression associated with strong intracellular immunostaining was most frequently detected in malignant (100%) than benign nodules (50%; P = 0.005). NIS protein was located at the basolateral membrane in 24% of the control samples, 8.3% of the benign, and 15.4% of the malignant nodules. The percentage of benign nodules with strong TSH receptor positivity (41.6%) was higher than malignant (7.7%). CONCLUSION We confirmed that reduced NIS mRNA expression in thyroid malignant nodules is associated with strong intracellular protein staining and may be related to the inability of the NIS protein to migrate to the cellular basolateral membrane. These results may explain the low iodide uptake of malignant nodules.

Moléstias associadas à carência crônica de iodo

The thyroid gland promotes its adaptation to iodine deficiency inducing an increase in the iodine uptake followed by a substantial increase in the thyroid gland mass (goiter). Simultaneously, there is a preferential T3 secretion by the follicular cell and a persistently elevated serum TSH. Laboratory tests, isotopic methods and imaging are routinely used to verify the altered thyroid pathophysiology. In certain populations the presence of goitrogenic natural substances, present in the locally consumed staple food, were found and may add to the pathogenic process. Endemic cretinism is usually present when the iodine deficiency is quite low and may present with the neurologic or myxedematous sub-types, frequently associated with deafmutism. In Brazil, the prevalence of iodine-deficiency disorders has been evaluated, periodically, with schoolchildren examined for goiter. Universal salt iodination was implemented in Brazil in the early fifties but recently the system was considered effective for the supply of iodine to the Brazilian population.

Prevalence and characteristics of postpartum thyroid dysfunction in São Paulo, Brazil

Postpartum thyroid dysfunction (PPTD) is an autoimmune disorder characterized by the development of transient hyperthyroidism and, more frequently, hypothyroidism (or both) during the first six months of the puerperal period. A variable incidence has been reported in part because of differences in the number of women studied, the frequency of thyroid assessment postpartum, diagnostic criteria and methodology. The aim of this study was to evaluate thyroid function, ultrasound images and titre of autoantibodies against thyroid antigens in a cohort of pregnant women who met the criteria of ‘normal’ thyroid gland structure on clinical examination and imaging and normal thyroid function tests without a significantly positive anti‐thyroid peroxidase (TPO) antibody titre (i.e. < 100 U/ml) in the first trimester.