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Objective: The intake of adequate amounts of iodine during pregnancy is essential for the neurological development of the fetus. The aim of this study was to assess iodine nutrition status in pregnant women from the state of São Paulo, Brazil., Material and Methods: We analyzed urinary iodine concentration (UIC) in 191 pregnant and 58 non-pregnant women matched by age. We used the World Health Organization criteria to define sufficient iodine supply (median UIC: 150-249 µg/L among pregnant women, and 100-199 µg/L for non-pregnant women)., Results: Median UIC of the pregnant women studied was lower than the recommended value (median = 137.7 µg/L, 95% CI = 132.9 - 155.9), while non-pregnant women had UIC levels within the appropriate range (median = 190 μg/L; 95% IC = 159.3-200.1). UIC was below 150 µg/L in 57% of the pregnant women., Conclusions: Although a larger sample is needed to consolidate these findings, these results raise concerns about the adequacy of the iodine supply of pregnant women in Brazil, especially considering the new determinations of the Brazilian government, which have recently reduced the concentrations of iodine in table salt to 15-45 mg/kg of salt.

Background: HLA-G is a nonclassical major histocompatibility complex molecule that has well-recognized immunomodulatory properties. The expression of HLA-G in tumor cells has been considered to be detrimental, permitting tumor spreading and decreased survival. We evaluated the expression of HLA-G in histologically normal thyroid tissue, goiter, and benign and malignant thyroid tumors, and studied the relationship between HLA-G expression and patient clinical variables., Patients and Methods: The immunohistochemistry expression of HLA-G was performed on 72 specimens of papillary thyroid carcinoma (PTC), 19 follicular thyroid carcinomas (FTC), 22 follicular adenomas (FA), 22 colloid goiters (CG), and 14 histologically normal thyroid glands (NT). The percentage of HLA-G staining was graded from absent (-) to intense (+++)., Results: HLA-G was faintly expressed in areas of hyperplasia in NT and CG. In PTC, FTC, and FA, the percentage of cell staining was significantly higher than in NT and CG (p<0.001 for each comparison). The tumor area with HLA-G expression was greater in FTC (p=0.0059) and PTC (p=0.0330) compared to FA. According to the magnitude of HLA-G staining, PTC tumors >1 cm exhibited increased HLA-G staining when compared to smaller tumors (p=0.03). Aggressive histologic subtypes of PTC have a higher median stained tumor area. No association was found between HLA-G expression and tumoral staging or patient disease-free survival., Conclusions: The gradual increase of HLA-G expression from hyperplasia to carcinomas, and the association of strong HLA staining with some variables implicated in poor prognosis corroborate the unfavorable role of HLA-G in tumor thyroid cells, inhibiting cytotoxic immune system cells and facilitating tumor evasion and progression.

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, with an incidence of 1:2,000 to 1:4,000 live births and it is a leading preventable mental retardation. Neonatal Screening Programs allow early identification of the disease and the adequate treatment of affected children can avoid the complications related to deprivation of the hormone. Most cases of primary congenital hypothyroidism (85%) are due to thyroid dysgenesis (ectopia, hypoplasia or agenesis) while the remaining result from defects in hormone synthesis. Affected children (> 95%) usually have no symptoms suggesting the disease at birth. The most frequent symptoms and signs are prolonged neonatal jaundice, hoarse cry, lethargy, slow movements, constipation, macroglossia, umbilical hernia, large fontanelle, hypotonia and dry skin. Around the world, various strategies are used for the screening of the CH. In Brazil, screening for CH is mandatory by law and usually done by serum TSH in dried blood collected from the heel. The recommended age for performing this test is after 48 hours of life until the 4th day. Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum.

Background: Primary hyperparathyroidism occurs in only 10%-30% of patients with multiple endocrine neoplasia type 2A (MEN2A), rarely as the sole clinical manifestation, and is usually diagnosed after the third decade of life., Summary: A 5-year-old girl was referred for prophylactic thyroidectomy as she carried the p.C634R RET mutation. She was clinically asymptomatic, with a normally palpable thyroid and with the cervical region free of lymphadenopathy or other nodules. Preoperative tests revealed hypercalcemia associated with elevation of parathyroid hormone (PTH) (calcium = 11.2 mg/dL, calcium ion = 1.48 mmol/L, phosphorus = 4.0 mg/dL, alkaline phosphatase = 625 U/L, parathyroid hormone (PTH) PTH = 998 pg/mL). A thyroid ultrasound was normal and parathyroid scintigraphy with (99m)Tc-Sestamibi revealed an area of radioconcentration in the upper half of the left thyroid lobe suggesting hyperfunctioning parathyroid tissue. She underwent total thyroidectomy and parathyroidectomy and developed hypocalcemia. The anatomopathological examination showed no histopathological changes in the thyroid tissue and an adenoma of the parathyroid gland, confirming the diagnosis of hyperparathyroidism., Conclusions: Primary hyperparathyroidism can be a precocious manifestation of MEN2A. This case report highlights that asymptomatic hypercalcemia should be scrutinized in children related to patients with MEN2A who carry a mutation in the RET proto-oncogene, especially mutations in the codon 634, before the currently recommended age of 8 years.

We report the clinical and laboratory findings, and molecular analysis of a Brazilian patient with resistance to thyroid hormone syndrome (RTH) detected by neonatal screening. The index case was born at term by normal delivery with 2,920 g and 45 cm. TSH of the neonatal screening test performed on the 5(th) day of life was of 13.1 µU/mL (cut-off = 10 µU/mL). In a confirmatory test, serum TSH level was 4.3 µU/mL, total T4 was 19 µg/dL (confirmed in another sample, Total T4 = > 24.0 µg/dL), free T4 was 3.7 ηg/dL, and free T3 was 6.7 pg/mL. Direct sequencing of the beta thyroid hormone receptor gene revealed mutation c.1357C>A (P453T), confirming the diagnosis of RHT. Family study demonstrated the presence of RTH in his 1-year-and-3-month-old sister, in his 35-year-old father, and in his 68-year-old paternal grandfather. All of them had goiter and only his father had received an erroneous diagnosis of hyperthyroidism. The present case shows that clinical evaluation and a judicious interpretation of total T4/free T4 concentrations in a newborn recalled due to slightly altered neonatal TSH can contribute to the diagnosis of RTH.

Amiodarone-induced thyroid dysfunction (AITD) is a common complication of amiodarone therapy and its prevalence varies according to iodine intake, subclinical thyroid disorders and the definition of AITD. There is no consensus about the frequency of screening for this condition. We evaluated 121 patients on chronic regular intake of amiodarone (mean intake = 248.5 +/- 89 mg; duration of treatment = 5.3 +/- 3.9 years, range = 0.57-17 years) and with stable baseline cardiac condition. Those with no AITD were followed up for a median period of 3.2 years (range: 0.6-6.7) and the incidence rate of AITD, defined by clinical and laboratorial findings as proposed by international guidelines, was obtained (62.8 per 1000 patients/year). We applied the Cox proportional hazard model to adjust for potential confounding factors and used sensitivity analysis to identify the best screening time for follow-up. We detected thyroid dysfunction in 59 (48.7%) of the 121 patients, amiodarone-induced hypothyroidism in 50 (41.3%) and hyperthyroidism in 9 (7.5%). Compared with patients without AITD, there was no difference regarding dosage or duration of therapy, heart rhythm disorder or baseline cardiac condition. During the follow-up of the 62 patients without AITD at baseline evaluation, 11 developed AITD (interquartile range, IR: 62.8 (95%CI: 31.3-112.3) cases per 1000 patients/year), 9 of them with hypothyroidism - IR: 11.4 (95%CI: 1.38-41.2), and 2 hyperthyroidism - IR: 51.3 (95%CI: 23.4-97.5). Age, gender, dose, and duration of treatment were not significant after adjustment. During the first 6 months of follow-up the incidence rate for AITD was 39.3 (9.2-61.9) cases per 1000 patients/year. These data show that AITD is quite common, and support the need for screening at 6-month intervals, unless clinical follow-up dictates otherwise or further information regarding the prognosis of untreated subclinical AITD is available.

The Neonatal Screening Program at the University Hospital of the Ribeirão Preto School of Medicine, São Paulo University, Brazil, was introduced in 1994. As of December 2005, congenital hypothyroidism had been diagnosed in 76 infants, phenylketonuria in 10, and hemoglobinopathies in 25, representing incidence rates of 1:2,595, 1:19,409, and 1:4,120, respectively. A total of 2,747 newborns had the sickle cell trait, i.e., were heterozygous for the sickle mutation (1:37.5 live births). The program's mean coverage during this period was 94.5%. There was major improvement in the parameters for evaluating the program's quality, although they were still far from ideal. Public-awareness campaigns on the importance of neonatal screening are needed to increase the program's coverage. Setting postnatal day 3 as the standard Day for the Heel Stick Test would help ensure treatment at earlier ages, thus improving prognosis for affected infants.

Objective: To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation., Methods: We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH., Results: A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 microg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH., Conclusion: This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than beta receptor of thyroid hormone (TRbeta) might modulate the phenotype of RTH.

Pregnancy is associated with an increased requirement of hormone secretion by the thyroid, within the first weeks after conception. To this greater demand to occurs, pregnancy induces a series of physiological changes that affect thyroid function and, consequently, the tests of glandular function. For normal pregnant women living in areas with a sufficient supply of iodine, this challenge regarding the adjustment of thyroid hormone releases to this new state of equilibrium and its maintenance until the end of pregnancy it meets no difficulties. However, among women with impaired thyroid function due to some thyroid disease or among women residing in areas with an insufficient iodine supply, this does not occur. The management of thyroid dysfunction during gestation requires special considerations, since both hypothyroidism and hyperthyroidism can lead to maternal and fetal complications. In addition, thyroid nodules are detected at reasonable frequency among pregnant women, a fact that requires a differential diagnosis between benign and malignant growths during the pregnancy itself.

The clinical and diagnostic aspects of cystic fibrosis have been extensively reviewed, with an emphasis on neonatal screening. This systematic literature review involved a search for relevant contributions in the PubMed and SciELO databases. The first references to cystic fibrosis date to the Middle Ages. Cystic fibrosis is the most frequent autosomal recessive hereditary disease among Caucasians (1:2,000 to 3,500). More than 1,000 mutations lead to the disease, the most common being "F508, with 70% prevalence among Canadian, Northern European, and American Caucasians and 23 to 55% prevalence among Brazilians. The basic defect is in chloride ion secretion. Cystic fibrosis screening has long been controversial, and after almost three decades, there are few nationwide programs (most are regional or local). However, the U.S. Centers for Disease Control and Prevention (CDC) has concluded that screening for cystic fibrosis is justified. The lack of a specific screening test and the ethnic heterogeneity of the Brazilian population pose challenges for neonatal screening.

Objective: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of reduced tissue responsiveness to thyroid hormone usually due to mutations located in the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor beta (TRbeta). In the present report we describe the clinical and laboratory characteristics and the genetic analysis of patients with this rare disorder from a Brazilian population., Patients: Four unrelated Brazilian families with diagnosis of RTH were studied. Age at diagnosis varied from 14 months to 29 years., Results: All affected individuals were clinically euthyroid, except for one patient who presented immediately after birth with hyperthyroidism. All individuals had tachycardia and goitre, elevated concentrations of free thyroid hormones and reduced sensitivity to thyroid hormone. Direct sequencing analysis of the TRbeta gene revealed four previously reported mutations: c.949G-->A, c.1313G-->A, c.1357C-->A and c.1358dupC in families A, B, C and D, respectively., Conclusion: The present report shows that the frequent mutations described in the thyroid hormone receptor worldwide are also present in the Brazilian population, which is characterized by a variable ethnic background.

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

The functional status of pituitary-gonadal hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous (LL/BL) and tuberculoid (TT/BT) poles of leprosy were investigated. Gonadotropins [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and C-reactive protein (CRP) concentrations and erythrocyte sedimentation rate (ESR) were significantly higher in LL/BL leprosy patients than in controls and were not different from controls in TT/BT patients. LH and FSH were positively correlated with IL-1beta, IL-6 and TNF-alpha, and CRP concentrations and ESR. Testosterone plasma levels were significantly decreased in LL/BL patients and not different in TT/BT patients compared with controls. In addition, testosterone levels were inversely correlated with IL-6 and TNF-alpha. Prolactin plasma levels of both LL/BL and TT/BT patients were not different when compared with those of controls. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. The significant correlations between gonadotropins and testosterone and cytokines in leprosy patients suggest that cytokines may have a direct influence at testicular level and may be of pathogenetic significance in leprosy and in other inflammatory states involving reproductive dysfunction.

Medullary thyroid carcinoma (MTC) occurs in a sporadic or as an autosomal dominant hereditary form. Inherited forms of MTC are related to mutations in the RET proto-oncogene. We screened genomic DNA from 11 patients with MTC for mutations in exons 10, 11, 13, 14, 15, and 16 of the RET proto-oncogene. Subsequently, we also evaluated a family of 1 patient with presumed diagnosis of sporadic MTC. Three patients with MEN2A from two unrelated families presented mutations in exon 11 (C634Y and C634R). A heterozygous mutation in exon 14 (V804M) was identified in the patient with the presumed sporadic MTC. We also observed two different polymorphisms: S904S in exon 15 (2 patients) and L769L in exon 13 (4 patients). The L769L polymorphism has been associated with earlier onset of sporadic MTC. On the other hand, mutations in exon 14 are associated with MTC of later onset and lower aggressiveness. Indeed, the carrier of the V804M mutation associated with L769L polymorphism presented MTC at 32 years of age, in contrast to her asymptomatic mother, who had only the V804M mutation and had MTC diagnosed by fine-needle aspiration biopsy at 60 years of age. In conclusion, the present study confirms the need for genetic screening to differentiate sporadic and hereditary forms of MTC. In addition, the genetic study allows the identification of asymptomatic carriers of hereditary forms of MTC. Finally, we speculated that the L769L polymorphism of the RET proto-oncogene may be related to earlier age of onset in the patient with the V804M mutation.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous and tuberculoid poles of leprosy were investigated. Interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha plasma levels, C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates (ESR) were significantly higher in LL/BL (lepromatous) leprosy patients than in control subjects. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulphate (DHEA-S) plasma levels were significantly lower in leprosy patients than in sex-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6, TNF-alpha, and CRP concentrations. This finding may be of pathogenetic significance in this disease and in other inflammatory states.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in paracoccidioidomycosis were investigated in a prospective study. Patients were evaluated before treatment and 1 and 6 months after receiving antifungal therapy. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha plasma levels, C-reactive protein (CRP) concentrations, and erythrocyte sedimentation rate (ESR) were significantly higher in untreated patients than in control subjects. After 6 months of treatment, levels of the 3 cytokines, CRP concentrations, and the ESR decreased significantly. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) plasma levels were significantly lower in patients than in sex- and age-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6 plasma levels. This finding may be of pathogenetic significance in this disease and in other inflammatory states.