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The study aimed to further characterise HLA encoded risk factors of type 1 diabetes (T1D) in Brazilian population and test the capability of a low resolution full-house DR-DQ typing method to find subjects at diabetes risk. Insulin and CTLA-4 gene polymorphisms were also analysed. The method is based on an initial DQB1 typing supplemented by DQA1 and DR4 subtyping when informative. Increased frequencies of both (DR3)-DQA1*05-DQB1*02 and DRB1*04-DQA1*03-DQB1*0302 haplotypes were detected among patients. DRB1*0401, *0402, *0404 and *0405 alleles were all common in DQB1*0302 haplotypes and associated with T1D. (DRB1*11/12/1303)-DQA1*05-DQB1*0301, (DRB1*01/10)-DQB1*0501, (DRB1*15)-DQB1*0602 and (DRB1*1301)-*0603 haplotypes were significantly decreased among patients. Genotypes with two risk haplotypes or a combination of a susceptibility associated and a neutral haplotype were found in 78 of 126 (61.9%) T1D patients compared to 8 of 75 (10.7%) control subjects (P< 0.0001). Insulin gene −2221 C/T polymorphism was also associated with diabetes risk: CC genotype was found among 83.1% of patients compared to 69.3% of healthy controls (P= 0.0369, OR 1.98) but CTLA-4 gene +49 A/G polymorphism did not significantly differ between patients and controls. Despite the diversity of the Brazilian population the screening sensitivity and specificity of the used method for T1D risk was similar to that obtained in Europe.

As síndromes de neoplasias endócrinas múltiplas (NEM) incluem as do tipo 1 (MEN 1) e 2 (MEN 2), a síndrome de von Hippel-Lindau, neurofibromatose tipo 1 e o complexo de Carney. Estas são síndromes genéticas complexas decorrentes de ativação ou inativação de diferentes tipos de genes envolvidos na regulação da proliferação celular. Nesta revisão, discutiremos as manifestações clínicas e o acompanhamento da MEN 1, assim como o rastreamento genético de potenciais portadores de alterações no gene MEN 1. A MEN 1 inclui o desenvolvimento de hiperparatiroidismo primário multifocal, tumores de ilhotas pancreáticas e adenomas de hipófise. Além disso, alguns pacientes podem apresentar manifestações cutâneas como angiofibromas e colagenomas e ainda podem desenvolver outras neoplasias como tumores carcinóides, tumores de tiróide, adenomas de adrenal, lipomas, feocromocitomas e meningiomas. A MEN 1 é uma síndrome hereditária, transmitida de forma autossômica dominante e causada por mutação inativadora do gene MEN 1. O gene MEN 1 codifica uma proteína denominada "menin", que é um gene supressor tumoral. Vários estudos demonstraram sua importância na regulação da proliferação celular e confirmaram seu papel na patogênese da MEN 1. A identificação do gene MEN 1 e sua análise genética resultaram na possibilidade de monitoração de pacientes que ainda não apresentam manifestações clínicas associadas a esta síndrome e diagnóstico precoce e tratamento dos pacientes afetados. Tais medidas poderão implicar em sobrevida maior para estes pacientes. Estudos adicionais visando uma melhor compreensão da função e dos mecanismos de sinalização da proteína "menin" poderão propiciar alternativas terapêuticas para os pacientes que evoluem com malignização de tumores relacionados à MEN 1, podendo resultar em maior sobrevida.

The Vitamin D endocrine system regulates multiple aspects of calcium metabolism and cellular differentiation and replication in the immune system, endocrine pancreas, liver, skeletal muscles and adipocytes. It plays an important role in glucose homeostasis, notably, in the mechanism of insulin release. Actions of vitamin D are mediated by the binding of 1, 25-(OH)2D3 to a specific cytosolic/nuclear vitamin D receptor (VDR), a member of the steroid/thyroid hormone receptor superfamily. Several frequent polymorphisms are found in the VDR gene and were reported to be associated with a variety of physiological and pathological phenotypes in many populations. In this paper, we will review the evidences suggesting associations of allelic variations in the VDR gene and phenotypes related to body weight, glucose homeostasis, diabetes and its vascular complications.

In contrast to most developed countries, most patients with primary hyperparathyroidism in Brazil are still symptomatic at diagnosis. However, we have been observing a change in this pattern, especially in the last few years. We evaluated 104 patients, 77 females and 27 males aged 11-79 years (mean: 54.4 years), diagnosed between 1985 and 2002 at a University Hospital. Diagnosis was made on the basis of clinical findings and of high total and/or ionized calcium levels, high or inappropriate levels of intact parathyroid hormone and of surgical findings in 80 patients. Patients were divided into three groups, i.e., patients diagnosed from 1985 to 1989, patients diagnosed from 1990 to 1994, and patients diagnosed from 1995 to 2002. The number of new cases diagnosed/year increased from 1.8/year in the first group to 6.0/year in the second group and 8.1/year in the third group. The first group comprised 9 patients (mean serum calcium ± SD, 13.6 ± 1.6 mg/dl), 8 of them (88.8%) defined as symptomatic. The second group comprised 30 patients (mean calcium ± SD, 12.2 ± 1.63 mg/dl), 22 of them defined as symptomatic (73.3%). The third group contained 65 patients (mean calcium 11.7 ± 1.1 mg/dl), 34 of them symptomatic (52.3%). Patients from the first group tended to be younger (mean ± SD, 43.0 ± 15 vs 55.1 ± 14.4 and 55.7 ± 17.3 years, respectively) and their mean serum calcium was significantly higher (P < 0.05). All of symptomatic patients independent of group had higher serum calcium levels (12.4 ± 1.53 mg/dl, N = 64) than asymptomatic patients (11.4 ± 1.0 mg/dl, N = 40). Our data showed an increase in the percentage of asymptomatic patients over the years in the number of primary hyperparathyroidism cases diagnosed. This finding may be due to an increased availability of diagnostic methods and/or to an increased awareness about the disease. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Medicina Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço UNIFESP, EPM, Depto. de Medicina UNIFESP, EPM, Depto. de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço SciELO

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are consequent to inactivating mutations of the calcium-sensing receptor (CaR) gene. FHH is usually associated with heterozygous inactivating mutations of the CaR gene, whereas NSHPT is usually due to homozygous inactivation of the CaR gene. FHH is generally asymptomatic and is characterized by mild to moderate lifelong hypercalcemia, relative hypocalciuria, and normal intact PTH, whereas individuals with NSHPT frequently show life-threatening hypercalcemia. In this study, we report a novel inactivating mutation of the CaR gene, identified in a 9-yr-old Brazilian girl who was found to be severely hypercalcemic during investigation of a 6-month history of headaches and vomits. Direct sequencing of the CaR gene from this patient showed a novel homozygous mutation (L13P) in exon 2. Functional characterization by intracellular calcium measurement by fluorometry showed that the mutant receptor had a dose-response curve shifted to the right relative to that of wild type. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, showed the same mutation in the heterozygous form. The mutation described in this study is the inactivating missense mutation present at the most N-terminal end among the known CaR missense mutations. This study reinforces the fact that patients with homozygous inactivation of the CaR gene may present with severe hypercalcemia in different phases of life.

A gravidez é acompanhada por uma série de modificações fisiológicas que incluem uma elevação significativa da globulina ligadora de tiroxina (Thyroxine-Binding Globulin, TBG). Tal elevação interfere nos níveis séricos totais da tiroxina (T4) e corrobora a utilização da medida de tiroxina livre (T4L), em conjunto com a dosagem de TSH, como métodos de primeira linha para a avaliação de função tiroidiana na gravidez. Uma definição cuidadosa dos valores normais de T4L durante a gestação é fundamental para o estudo de alterações da função tiroidiana, desde que disfunções mínimas podem resultar em anormalidades fetais significativas. Estudamos 132 grávidas normais, entre 6 e 38 semanas de gestação, e os resultados da medida de T4L por método indireto em duas etapas (valores normais de 0,7 a 1,5ng/dL em não grávidas, n= 797) mostraram valores entre 0,5 e 1,3ng/dL, com média±DP de 0,78±0,16ng/dL, significativamente mais baixos que os observados em não grávidas (0,98±0,14ng/dL, P

A calcitonina é um hormônio secretado pelas células parafoliculares tiroideanas. O diagnóstico de carcinoma medular de tiróide (CMT) pode ser suspeitado a partir do encontro de níveis aumentados de calcitonina basal ou após testes de estímulos específicos. Neste sentido, a calcitonina caracteriza-se como um importante marcador tumoral para o diagnóstico e seguimento de pacientes portadores de CMT. Neste artigo, revisamos alguns tópicos referentes à utilidade da dosagem de calcitonina basal em pacientes portadores de nódulos de tiróide para rastreamento de CMT. Comentamos a respeito dos principais testes de estímulo para secreção de calcitonina disponíveis e finalizamos com algumas observações sobre os ensaios para dosagem de calcitonina. Calcitonin is a hormone secreted by the parafollicular thyroid cells. Diagnosis of medullary thyroid carcinoma (MTC) should be considered when high basal calcitonin levels or high calcitonin levels after specific provocative test are found. In this context, calcitonin is considered a relevant tumor marker for diagnosis and follow-up of MTC. In this manuscript, we review some issues related to the usefulness of measuring basal calcitonin in patients with thyroid nodules. The current available provocative tests for calcitonin are discussed. Finally, we comment on some aspects related to the assays for calcitonin measurement.

Data obtained during the past five years have indicated that there are important age- and gender-based differences in the regulation and action of leptin in humans. To study the physiological changes of leptin during puberty in both sexes, and its relationship with body composition and sexual maturation, we measured leptin concentrations in 175 healthy adolescents (80 girls, 95 boys, 10-18 years of age), representing all pubertal stages. We excluded individuals with a body mass index (BMI) below the 5th or above the 95th percentile relative to age. Serum concentrations of leptin were determined by a monoclonal antibody-based immunofluorimetric assay, developed in our laboratory. Body composition was determined by dual-energy X-ray absorptiometry. Pubertal stage was assigned by physical examination, according to Tanner criteria for breast development in females and genital development in males. Leptin concentration in girls (N = 80) presented a positive linear correlation with age (r = 0.35, P = 0.0012), BMI (r = 0.65, P < 0.0001) and %fat mass (r = 0.76, P < 0.0001). In boys (N = 95) there was a positive correlation with BMI (r = 0.49, P < 0.0001) and %fat mass (r = 0.85, P < 0.0001), but a significant negative linear correlation with Tanner stage (r = -0.45, P < 0.0001) and age (r = -0.40, P < 0.0001). The regression equation revealed that %fat mass and BMI are the best parameters to be used to estimate leptin levels in both sexes. Thus, the normal reference ranges for circulating leptin during adolescence should be constructed according to BMI or %fat mass to assure a correct evaluation.

Summary objective Hyperprolactinaemia is caused by high levels of monomeric, dimeric or macro forms of prolactin in circulation, the monomeric form being predominant in patients with prolactinomas. Macroprolactinaemia, however, is common and is associated with asymptomatic cases. In this study, we reviewed our records regarding clinical and imaging investigations in patients who were found to have hyperprolactinaemia predominantly due to the presence of macroprolactin and compared them with the findings observed in patients whose prolactin molecular size consisted predominantly of the monomeric form. patients and methods We conducted a retrospective study of 113 consecutive patients (nine men and 104 women, aged 19–67 years, median age 39 years) with hyperprolactinaemia who were screened for the presence of macroprolactin by polyethylene glycol precipitation and/or chromatography and submitted to pituitary magnetic resonance imaging (MRI) and/or computerized tomography (CT). results Fifty-two of 113 patients (46%) had hyperprolactinaemia due to macroprolactin, whereas the remaining 61 patients (54%) had their hyperprolactinaemia confirmed by the predominance of the monomeric form. Both groups shared similar mean prolactin levels (79·9 ± 63·6 µg/l, median of 62·0 µg/l, and 97·9 ± 155·4 µg/l, median of 61·0 µg/l, respectively). Of the patients with macroprolactinaemia, 46% had no symptoms of hyperprolactinaemia, whereas only 10% of the patients who screened negative for macroprolactin were asymptomatic. There was an association between macroprolactinaemia and negative pituitary imaging findings: normal pituitary images were found in 78·9% of patients who had macroprolactinaemia and in 25% of patients with monomeric hyperprolactinaemia. In addition, none of the patients with macroprolactinoma (seven cases) had macroprolactinaemia. conclusions The presence of macroprolactinaemia does not exclude the possibility of a pituitary adenoma and consequently may not prevent pituitary imaging studies. However, our data demonstrate that all asymptomatic patients who screened positive for macroprolactin had normal pituitary imaging studies. Patient samples showing hyperprolactinaemia should be first tested for macroprolactin, before the patient is submitted to imaging studies. We suggest that imaging studies should be ordered in patients with macroprolactinaemia when indicated by clinically relevant features. As a result, unnecessary anxiety and costly medical procedures may be prevented.

O receptor sensível ao cálcio extracelular (CaR) é um receptor acoplado à proteína G (GPCR), que exerce um papel essencial na regulação da homeostase do cálcio extracelular. O CaR encontra-se expresso em todos os tecidos relacionados com o controle desta homeostase (paratiróides, células C tiroideanas, rins, intestino e ossos). Logo após a clonagem do CaR, mutações inativadoras e ativadoras do gene deste receptor foram associadas com doenças genéticas humanas: hipercalcemia hipocalciúrica familiar (FHH) e hiperparatiroidismo neonatal severo (NSHPT) são causados por mutações inativadoras do gene do CaR, enquanto que a hipocalcemia autossômica dominante é resultante de mutações ativadoras do gene do CaR. Apesar de raras, tais doenças devem ser consideradas no diagnóstico diferencial de distúrbios hipercalcêmicos e hipocalcêmicos. O reconhecimento do papel fundamental do CaR na manutenção da homeostase do cálcio extracelular motivou o desenvolvimento de drogas capazes de modular a função do CaR, ativando-o (drogas calcimiméticas) ou inativando-o (drogas calciolíticas). Tais drogas têm uma implicação terapêutica potencial, como o controle clínico de casos específicos de hiperparatiroidismo primário e urêmico com o uso de drogas calcimiméticas e um tratamento promissor para osteoporose com o uso de drogas calciolíticas.

O carcinoma de paratiróide é uma entidade rara, havendo cerca de 535 casos descritos na literatura. Neste trabalho, revisamos a nossa casuística de 5 pacientes com carcinoma de paratiróide avaliados no período de 1983 a 1998 no serviço de Doenças Ósteo-Metabólicas da Universidade Federal de São Paulo, analisando critérios diagnósticos, conduta terapêutica e a evolução destes pacientes e comparando os nossos dados com os achados de literatura. Entre os nossos pacientes, 4 eram do sexo feminino e 1 do sexo masculino, com mediana ao diagnóstico de 52 anos de idade, variando de 10 a 77 anos. As queixas iniciais incluíam presença de dores ósseas acompanhada de perda de peso em 4 pacientes, presença de fratura não traumática em 3 pacientes e traumática em 2 e clínica de nefrolitíase em 1 paciente. Todos apresentavam nódulo palpável em região cervical, níveis de cálcio total bastante elevados com média(±DP) de 14,9±1,7mg/dL. PTH também se encontrava muito elevado, refletindo a magnitude da severidade da doença. Todos foram submetidos à exploração cirúrgica cervical com retirada da massa tumoral, que foi coincidente com o achado palpatório de nódulo cervical. O exame anátomo-patológico revelou o diagnóstico de carcinoma de paratiróide em todos estes casos. No seguimento, 2 pacientes apresentaram recidiva tumoral e evoluíram para óbito por complicações do hiperparatiroidismo. Os outros 3 casos encontram-se em acompanhamento ambulatorial no nosso hospital, sem evidências até o momento de recidiva tumoral.

CONTEXTO: Acredita-se que por volta de 25% das mulheres menopausadas nos EUA venham a sofrer de alguma fratura óssea em decorrência da osteoporose. Fraturas proximais de fêmur são associadas com maior número de mortes, incapacidade e custo médico maior do que as outras fraturas osteoporóticas juntas (vertebral e rádio distal). OBJETIVO: Avaliar características clínicas e epidemiológicas de pacientes com fratura proximal de fêmur em hospitais de São Paulo. TIPO DE ESTUDO: Transversal retrospectivo. LOCAL: Hospital São Paulo e Hospital do Servidor Público Estadual Francisco Morato Oliveira. PARTICIPANTES: Pacientes com idade igual ou superior à 65 anos, internados com fratura proximal de fêmur nos hospitais acima citados entre março e novembro de 1996 (n = 73). Esse grupo foi comparado a pacientes ambulatoriais, de mesma idade, sem fratura proximal de fêmur (n = 50). INTERVENÇÃO: Avaliação de dados antropométricos (peso, altura, índice de massa corpórea), hábitos de vida (atividade física, tabagismo, ingesta de cálcio, álcool e café), antecedentes ginecológicos (menarca, menopausa, gestações e amamentações), tipo de fratura, doenças concomitantes e medicações em uso. VARIÁVEIS ESTUDADAS: Para comparação dos diferentes hábitos entre os dois grupos, utilizamos o teste do Qui-quadrado; demais dados foram comparados por teste não paramétrico de Mann-Whitney; sendo significante P £ 0, 05. RESULTADOS: Observamos predomínio de fratura proximal de fêmur no sexo feminino (3, 3 mulheres/1 homem) com aumento progressivo da frequência de fratura proximal de fêmur com avançar da idade em ambos os sexos. O grupo com fratura proximal de fêmur comparado ao controle, apresentou menor índice de massa corpórea, menor atividade física, maior número de gestações e amamentações. Demais dados sem diferença estatística. CONCLUSÃO: Concordante com a literatura, constatamos um predomínio de fratura proximal de fêmur no sexo feminino, o efeito benéfico do índice de massa corpórea mais elevado e da atividade física na redução da freqüência de fratura proximal de fêmur. Salientamos ainda, o papel da gestação e lactação sobre as fraturas proximais de fêmur. CONTEXT: It is believed that about 25% of menopausal women in the USA will exhibit some kind of fracture as a consequence of osteoporosis. Fractures of the proximal femur are associated with a greater number of deaths and disabilities and higher medical expenses than all the other osteoporotic fractures together. OBJECTIVE: To study the clinical and epidemiological features of patients with proximal femur fracture in hospitals in São Paulo. DESIGN: Transversal and retrospective study. LOCAL: Hospital São Paulo and Hospital Servidor Público Estadual Francisco Morato Oliveira. PARTICIPANTS: Patients aged sixty-five years or more hospitalized because of proximal femur fracture, from March to November 1996 (N = 73). This group was compared to patients of the same age without fracture of the proximal femur. INTERVENTION: Evaluation of weight, height, body mass index; lifestyle habits (physical activity at home, ingestion of dairy calcium, drinking of coffee, smoking habit), gynecological history (ages at menarche and menopause, number of pregnancies and lactations), previous morbidity, use of medications, history of previous fractures, family history of osteoporosis. MEASUREMENT: The comparison of the different data regarding lifestyle habits between the two groups was made using the chi-squared test. Other data were analyzed using the Mann -- Whitney test. P £ 0.05 was considered significant. RESULTS: We noted a predominance of proximal femur fracture among females in relation to males (a female/male ratio of 3.3:1) with a progressive increase in the frequency of proximal femur fracture with age in both sexes. The group with proximal femur fracture, in comparison with the control group, showed a lower body mass index, less physical activity, and a greater number of pregnancies and lactations. Other data were not different. CONCLUSION: In accordance with the literature, we found a predomination of proximal femur fracture in women in relation to men, and a favorable effect of higher body mass index and physical activity for decreasing the frequency of proximal femur fracture. We also discuss the role of pregnancies and lactation on the frequency of proximal femur fracture. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Division of Endocrinology and Orthopedics Hospital do Servidor Público Estadual Division of Orthopedics UNIFESP, EPM, Division of Endocrinology and Orthopedics SciELO

The recently cloned extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones) and also in tissues with apparently no role in the maintenance of extracellular calcium levels, such as brain, skin and pancreas. The CaR amino acid sequence is compatible with three major domains: a long and hydrophilic aminoterminal extracellular domain, where most of the activating and inactivating mutations described to date are located and where the dimerization process occurs, and the agonist-binding site is located, a hydrophobic transmembrane domain involved in the signal transduction mechanism from the extracellular domain to its respective G protein, and a carboxyterminal intracellular tail, with a well-established role for cell surface CaR expression and for signal transduction. CaR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaR-activating mutations. Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug.

OBJECTIVE We have investigated the effects of the inhaled corticosteroid flunisolide on bone metabolism and adrenal function in patients with moderate asthma. SUBJECTS AND DESIGN Twenty ambulatory patients (13 females, 7 males, mean age ± SD of 36.4 ± 12.4 years) with moderate asthma were recruited. None had taken corticosteroids for at least 1 month. Flunisolide 500 μg was given twice a day for 10 weeks, without any other medication. Blood and urine were collected before and at the end of treatment course. Cortisol (basal and 1 h after ACTH 250 μg i.v.) was measured to evaluate adrenal function. A peak cortisol response of 496 nmol/l was considered an adequate response. Serum ionized calcium, intact PTH, plasma osteocalcin (OC) and urinary pyridinoline (Pyr) and deoxy-pyridinoline (D-Pyr) were measured to evaluate bone metabolism. Wilcoxon paired test was performed for statistical analysis. Results are expressed as mean ± SD. RESULTS In most patients (85%), there was no difference after treatment with flunisolide on basal and stimulated cortisol levels. We found a significant decrease of OC (3.55 ± 1.42 to 2.97 ± 1.05 nmol/l) and Pyr (66.4 ± 20.0 to 59.5 ± 24.9 pmol/μmol creatinine) levels after treatment (P

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) represent intermediate states between normal fasting glucose (NFG) or normal glucose tolerance (NGT), respectively, and diabetes (1). The regulation of fasting and glucose concentrations after an oral glucose load is dependent on different physiological mechanisms (2), and current evidence suggests that IFG and IGT have different pathophysiologies (3,4). Measurement of fasting plasma glucose (FPG) is the most frequently used screening test for diabetes. However, the oral glucose tolerance test (OGTT) might be a preferable test because FPG underestimates the severity of glucose intolerance (5,6) and because IFG and IGT define two distinct populations with only partial overlap (5,7,8). The present study was undertaken to compare insulin sensitivity and insulin secretion profiles associated with different stages of hyperglycemia as assessed by FPG only or by FPG and 2-h plasma glucose during an OGTT. We analyzed data from 900 subjects without previously known diabetes who underwent an OGTT for diagnostic purposes at Fleury Institute, Sao Paulo, Brazil. A double-glycemic status was determined for each subject. A first set was based on FPG only as follows: NFG (FPG …

The authors report the case of a chronic myeloid leukemia (CML) patient submitted to allogenic bone marrow transplantation, who had probably never entered complete remission. The disease was reactivated as a granulocytic sarcoma, next to a platinum plate installed to correct a tibia fracture 11 years earlier. Its final event was a myeloid Ph1+ blastic crisis that was unsuccessfully treated with high doses of sc interferon and citarabine.

As metodologias empregadas para a medida de TSH sérico apresentam níveis de especificidade e sensibilidade, tanto diagnósticas como analíticas, bastante elevadas. Adicionalmente, são metodologias bastante robustas, de maneira que resultados falso-positivos ou falso-negativos são raros e inesperados. Descrevemos neste trabalho dois casos de indivíduos descritos como eutiróideos, sem antecedentes de doenças autoimunes e sem referência ao uso de TSH exógeno, que apresentavam níveis de TSH de normais a muito elevados, dependendo da metodologia empregada. Em três métodos testados para a medida de TSH a diluição seriada das amostras mostrou que os níveis reais situavam-se entre 250 e 300 mUI/L. Nos dois casos, o aumento de TSH foi ocasionado pela presença de proteínas ligadoras de TSH no soro, formando formas de alto peso molecular ("macro TSH"), demonstradas por cromatografia de gel filtração em coluna de Superdex S-200. Em uma das pacientes a proteína ligadora foi caracterizada como IgG através de cromatografia em proteína G sepharose, na outra, a ligação em proteína G e em coluna de sepharose acoplada a monoclonal anti-IgM não conseguiu caracterizar a proteína ligadora sérica. Estes casos salientam a importância da correlação clínico-laboratorial e sugerem a necessidade de se pesquisar a presença de macro TSH em pacientes com níveis de TSH anormalmente elevados.

Conventional assessment of glycemic control in diabetes mellitus (DM) includes blood glucose attention to glycemia and glycated hemoglobin levels. Recently, we introduced the continuous glucose-monitoring test (CGM) (Medtronic Minimed-CGMS System Gold). Here we describe our experience with this methodology over the year 2004. A total of 141 CGM tests were performed over this period of time. Overall, 88% (n= 124) patients were diabetics (DM), 99 of them were insulin users. We found a strong correlation between glucose values obtained by CGM and capillary glucose measures (r= 0.926; p0.005). In diabetic patients, nocturnal hypoglycemia (50 mg/dL) was identified in approximately 35% (n= 44), hyperglycemic patterns (220 mg/dL) at specific times of day in approximately 44% and sustained hyperglycemia throughout the whole monitoring period in thirteen cases (10%). Twelve tests were performed to investigate the occurrence of hypoglycemia in non-diabetic subjects. Two tests came out very suggestive of "dumping", and in one case the CGMS supported the hypothesis of insulinoma. Partial monitoring interruptions have occurred in 15% of all tests. We concluded that CGMS is a useful methodology to investigate glycemic fluctuations, and it is also an important tool to adjust therapy in diabetic patients.

Parathyroid carcinoma is a rare condition, comprising less than 1% of the cases of primary hyperparathyroidism (PHP). Nonetheless, due to its aggressiveness, and having prognosis dependent on the precocity of diagnosis and radical therapeutic approach, it is paramount that the clinical suspicion be made before surgery. Clinical presentation is typical of severe PHP, with a parathyroid tumor1.5 cm, usually palpable. The pathologic features sometimes are difficult to characterize. Our experience with this condition (from 1983 to 2004) includes 7 cases, all symptomatic, hypercalcemic syndrome and bone disease present in most of them. In 6/7 the tumor was palpable, and in all the biochemical profile was compatible with severe PHP. Three patients died of complications of hypercalcemia. Recent findings point to a mutation on the gene HRPT2 as the molecular base for the development of this kind of tumor. The therapeutic approach is surgical and should include ipsilateral thyroidectomy and cervical exploration in order to find possible local metastasis. Post-surgical complications (mainly hypocalcemia) are proportional to the pre-existing metabolic alterations. The long-term prognosis depends upon the precocity of diagnosis, surgical success and control of hypercalcemia. New therapeutic approaches, based on bisphosphonates and calcimimetic drugs, as well as the possibility of genetic diagnosis, tend to ameliorate the prognosis of this severe affection.

Vitamin D deficiency, observed mainly in the geriatric population, is responsible for loss of bone mass and increased risk of bone fractures. Currently, recommended doses of cholecalciferol are advised, but since there are few studies evaluating the factors that influence the serum levels of 25-hydroxyvitamin D (25(OH)D) following supplementation, we analyzed the relationship between the increase in serum 25(OH)D after supplementation and body fat. We studied a group of 42 homebound elderly subjects over 65 years old (31 women) in order to assess whether there is a need for adjustment of the doses of cholecalciferol administered to this group according to their adipose mass. Baseline measurements of 25(OH)D, intact parathyroid hormone and bone remodeling markers (osteocalcin and carboxy-terminal fraction of type 1 collagen) were performed. Percent body fat was measured by dual-energy X-ray absorptiometry. The patients were divided into three groups according to their percent body fat index and were treated with cholecalciferol, 7,000 IU a week, for 12 weeks. The increases in serum levels of 25(OH)D were similar for all groups, averaging 7.46 ng/mL (P < 0.05). It is noteworthy that this increase only shifted these patients from the insufficiency category to hypovitaminosis. Peak levels of 25(OH)D were attained after only 6 weeks of treatment. This study demonstrated that adipose tissue mass does not influence the elevation of 25(OH)D levels following vitamin D supplementation, suggesting that there is no need to adjust vitamin D dose according to body fat in elderly homebound individuals. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Disciplina de Endocrinologia UNIFESP, EPM, Disciplina de Endocrinologia SciELO

Clonidine stimulation test is widely used to evaluate growth hormone secretion. Side effects are somnolence (35%) and arterial hypotension (AH) (5%). The aims of this paper were to evaluate the tolerance to this test regarding blood pressure (BP) decrease, sedation and the efficacy of saline resuscitation to prevent AH. BP was measured at basal, 60 and 120 min. Sedation was determined by the Ramsay scale. Patients were divided into two groups: Group 1 (n = 80) received saline resuscitation only upon severe AH (drop of mean BP [MBP]20% from initial MBP) and/or postural hypotension; Group 2 (n = 100) received saline resuscitation from the beginning of the test. Both groups presented a significant MBP fall and 75% presented somnolence at 60 min. MBP drop did not correlate with either sedation or the clonidine dose. Group 1 presented more hypotension (59% x 28%) and greater MBP drop at 60 min. Only one patient had an asthma attack. We conclude that the hypotension effects caused by oral clonidine diminish with saline resuscitation since the beginning of the test. This test must have specialized medical support with strict BP evaluation and precocious intervention when needed.

Summary Background NEUROD1 encodes a transcription factor expressed in the endocrine pancreas, and involved in beta-cell development, function and mechanisms of apoptosis. In this study, we investigated the association of a frequent polymorphism in exon 2 of NEUROD1 (G > A; Ala45Thr) with Type 1 diabetes in Brazilian subjects. Methods A population/association study comprising 246 unrelated Type 1 diabetic and 275 nondiabetic white Brazilian subjects. The Ala45Thr variant was genotyped by a PCR-RFLP method. Results The frequency of the Thr allele was significantly higher in patients with Type 1 diabetes than in controls (42.3% vs 35.3%, P = 0.02). Stratification by gender showed that homozygosity for the Thr allele was associated with Type 1 diabetes in women with odds ratio of 3.66 (95 % C.I. 1.43-10.11, P = 0.009) as compared to homozygosity for the Ala allele. This effect was not observed in men. Conclusions We found a gender-specific association of the Ala45Thr variant of NEUROD1 with Type 1 diabetes in Brazilian women. Our results suggest that gender as well as ethnicity might modulate the association of NEUROD1 with Type 1 diabetes.

A avaliação do controle glicêmico no diabetes mellitus (DM) envolve tradicionalmente a observação das taxas de glicemia e hemoglobina glicada. Recentemente o Fleury - Centro de Medicina Diagnóstica implantou o exame de monitorização contínua de glicose (MCG) (Medtronic Minimed - CGMS® System GoldTM) e, neste trabalho, objetivamos descrever a experiência relacionada à realização deste exame durante o ano de 2004. Realizaram-se 141 exames neste período. Do total, 88% (n= 124) pacientes eram diabéticos, sendo 99 usuários de insulina. Encontramos forte correlação entre os valores de glicose obtidos com a MCG e no sangue capilar (r= 0,926; p< 0,005). Nos diabéticos, identificou-se hipoglicemia noturna (< 50mg/dL) em ~35% (n= 44), padrões hiperglicêmicos (> 220mg/dL) em períodos determinados do dia em ~44% e hiperglicemia sustentada ao longo de toda monitorização em treze casos (10%). Doze exames foram realizados para investigação de hipoglicemias em não diabéticos. Dois exames foram sugestivos de "dumping" e em um caso a MCG reforçou a hipótese de insulinoma. Ocorreram interrupções parciais das monitorizações em 15% dos exames. Concluímos que a MCG é uma metodologia útil para investigação das oscilações glicêmicas, sendo uma importante ferramenta para ajuste terapêutico em pacientes com DM. Conventional assessment of glycemic control in diabetes mellitus (DM) includes blood glucose attention to glycemia and glycated hemoglobin levels. Recently, we introduced the continuous glucose-monitoring test (CGM) (Medtronic Minimed - CGMS® System GoldTM). Here we describe our experience with this methodology over the year 2004. A total of 141 CGM tests were performed over this period of time. Overall, 88% (n= 124) patients were diabetics (DM), 99 of them were insulin users. We found a strong correlation between glucose values obtained by CGM and capillary glucose measures (r= 0.926; p< 0.005). In diabetic patients, nocturnal hypoglycemia (< 50mg/dL) was identified in ~35% (n= 44), hyperglycemic patterns (> 220mg/dL) at specific times of day in ~44% and sustained hyperglycemia throughout the whole monitoring period in thirteen cases (10%). Twelve tests were performed to investigate the occurrence of hypoglycemia in non-diabetic subjects. Two tests came out very suggestive of "dumping", and in one case the CGMS supported the hypothesis of insulinoma. Partial monitoring interruptions have occurred in 15% of all tests. We concluded that CGMS is a useful methodology to investigate glycemic fluctuations, and it is also an important tool to adjust therapy in diabetic patients.

Carcinoma de paratiróide é uma condição rara, correspondendo na maior parte das casuísticas a menos de 1% dos casos de hiperparatiroidismo primário (HPP). No entanto, pela sua gravidade, e com o prognóstico dependente do diagnóstico precoce e de uma conduta agressiva, é fundamental que a suspeita clínica seja feita pré-operatoriamente. As características clínicas são compatíveis com um caso de HPP grave, sintomático, com tumor cervical >1,5cm, podendo ser palpável. A definição anátomo-patológica pode ser difícil em muitos casos. Nossa casuística (1983-2004) compreende 7 casos, todos sintomáticos, com síndrome hipercalcêmica e doença óssea presente na maioria. Em 6/7 o tumor era palpável, e todos apresentavam quadro bioquímico compatível. Três pacientes faleceram em quadro de hipercalcemia refratária. Dados recentes apontam para uma mutação no gene HRPT2 como base molecular para o desenvolvimento destes tumores. A conduta é cirúrgica e deve incluir hemitiroidectomia e exploração cervical ampliada, procurando focos metastáticos. O pós-operatório é compatível com a gravidade da alteração metabólica pré-existente, sendo comum a tendência a hipocalcemia. O prognóstico de longo prazo depende do diagnóstico precoce, do sucesso cirúrgico e do controle da hipercalcemia. Novas possibilidades terapêuticas, na forma de bisfosfonatos e drogas calcimiméticas, bem como a possibilidade de diagnóstico genético, tendem a melhorar o prognóstico desta grave condição. Parathyroid carcinoma is a rare condition, comprising less than 1% of the cases of primary hyperparathyroidism (PHP). Nonetheless, due to its aggressiveness, and having prognosis dependent on the precocity of diagnosis and radical therapeutic approach, it is paramount that the clinical suspicion be made before surgery. Clinical presentation is typical of severe PHP, with a parathyroid tumor >1.5cm, usually palpable. The pathologic features sometimes are difficult to characterize. Our experience with this condition (from 1983 to 2004) includes 7 cases, all symptomatic, hypercalcemic syndrome and bone disease present in most of them. In 6/7 the tumor was palpable, and in all the biochemical profile was compatible with severe PHP. Three patients died of complications of hypercalcemia. Recent findings point to a mutation on the gene HRPT2 as the molecular base for the development of this kind of tumor. The therapeutic approach is surgical and should include ipsilateral thyroidectomy and cervical exploration in order to find possible local metastasis. Post-surgical complications (mainly hypocalcemia) are proportional to the pre-existing metabolic alterations. The long-term prognosis depends upon the precocity of diagnosis, surgical success and control of hypercalcemia. New therapeutic approaches, based on bisphosphonates and calcimimetic drugs, as well as the possibility of genetic diagnosis, tend to ameliorate the prognosis of this severe affection.

The laboratory methods usually employed for the measurement of serum TSH present sensitivity and specificity levels, both analytical and clinical, are highly satisfactory. Additionally, the methodologies are quite robust, so that false-positive and false-negative results are rare and unexpected. In this paper we describe two individuals quoted as euthyroid clinically, with no reference to autoimmune diseases, and no reference to the use of exogenous TSH, that presented with normal to extremely high serum TSH levels, depending on the method employed for analysis. In the three tested methods, serial dilution showed that the real TSH levels were between 250 and 300 mUI/L. In both cases the increment in TSH levels were due to the presence of TSH-binding proteins, forming high molecular weight complexes ("macro TSH"), well characterized by gel filtration chromatography on Superdex S-200 column. In one of the patients the binding protein was characterized as being IgG by protein-G binding study. In the other case, protein-G binding as well as anti-IgM binding failed to characterize the protein. These two cases call attention to the importance of the clinical-laboratory correlation and suggest the need that the presence of "macro TSH" must be investigated in patients with unexpectedly high TSH values.

O teste da clonidina é amplamente usado para avaliar a secreção do hormônio do crescimento. Os efeitos colaterais são sonolência (35%) e hipotensão arterial (HA) (5%). Nossos objetivos foram avaliar a tolerância ao teste quanto à queda da pressão arterial (PA), grau de sedação e eficácia da expansão volêmica para controle da HA. A PA foi medida nos tempos basal, 60 e 120 min. A sedação foi baseada na escala Ramsay. Os pacientes foram divididos em dois grupos: o Grupo 1 (n= 80) recebeu expansão volêmica apenas com HA grave (queda da PA média [PAM] > 20% da PAM inicial) e/ou hipotensão postural; o Grupo 2 (n=100) recebeu expansão volêmica desde o início do teste. Nos dois grupos, a PAM caiu significativamente e 75% apresentaram sonolência aos 60 min. Não houve correlação da queda da PAM com grau de sedação e dose administrada. O Grupo 1 apresentou mais hipotensão (59% x 28%) e maior queda da PAM aos 60 min. Apenas um paciente apresentou broncoespasmo. Concluímos que o efeito hipotensor da clonidina diminui com expansão volêmica desde o início no teste. Este teste deve ser sempre feito com acompanhamento médico especializado para observação estrita da PA e intervenção precoce, se necessária. Clonidine stimulation test is widely used to evaluate growth hormone secretion. Side effects are somnolence (35%) and arterial hypotension (AH) (5%). The aims of this paper were to evaluate the tolerance to this test regarding blood pressure (BP) decrease, sedation and the efficacy of saline resuscitation to prevent AH. BP was measured at basal, 60 and 120 min. Sedation was determined by the Ramsay scale. Patients were divided into two groups: Group 1 (n= 80) received saline resuscitation only upon severe AH (drop of mean BP [MBP] > 20% from initial MBP) and/or postural hypotension; Group 2 (n= 100) received saline resuscitation from the beginning of the test. Both groups presented a significant MBP fall and 75% presented somnolence at 60 min. MBP drop did not correlate with either sedation or the clonidine dose. Group 1 presented more hypotension (59% x 28%) and greater MBP drop at 60 min. Only one patient had an asthma attack. We conclude that the hypotension effects caused by oral clonidine diminish with saline resuscitation since the beginning of the test. This test must have specialized medical support with strict BP evaluation and precocious intervention when needed.

Introduction of 2nd generation immunometric assays for the measurement of serum parathyroid hormone (PTH), turned them more available, simple and rapid. These methods, based on double identification of the PTH molecule, supposedly measure the intact, bioactive molecule, with the sequence 1-84. Recent works showed that they also measure forms with amino-terminal deletions, like the 7-84 form, which are not able to activate the traditional PTH receptor (PTH1R). Thus, an important practical aspect is the definition of the PTH forms measured by the immunometric assays, a fact that depends on the specificity of the antibodies employed. In this report we compare the results obtained with an in-house immunofluorometric assay that presents a cross-reactivity of 50% with the 7-84 PTH sequence, and two commercial 2nd generation assays, that react 100%. In a first study, 135 samples were measured using our assay and an electrochemiluminescent assay, resulting in a correlation coefficient of 0.961 (P0.0001) and medians of 35.0 and 51.0 ng/L (P0.0001). In a second study, 252 samples were analyzed using our assay and an immunochemiluminometric assay, resulting in a correlation of 0.883 (P0.0001) and medians of 36.0 and 45.5 ng/L (P0.0001). In both studies results obtained with the in-house assay were significantly lower, as expected by the specificity of the anti-amino-terminal antibody employed. Our data support the need of a precise description of the specificity of the amino-terminal antibodies employed in 2nd generation PTH assays in order to better compare results and define normal ranges.

Pregnancy induces a series of physiological modifications that include a significant elevation of thyroxine-binding globulin (TBG) levels. This elevation interferes in the serum levels of total thyroxine and stresses the use of free thyroxine (FT4), together with TSH measurement, as the first line tests in the evaluation of thyroid function in pregnancy. A careful definition of the normal values for FT4 during pregnancy is paramount for the study of thyroid abnormalities, since minimal dysfunctions can result in significant fetal abnormalities. We studied 132 normal pregnant women, from 6 to 38 weeks of gestation, and the serum FT4 measured by an indirect two-step assay (normal values for non-pregnant women: 0.7 to 1.5 ng/dL; mean+/-SD 0.98+/-0.14 ng/dL, n= 797) showed values between 0.5 and 1.3 ng/dL; mean+/-SD of 0.78+/-0.16 ng/dL, values significantly lower than the observed in non-pregnant women (P0.0001). Values tended to decline progressively throughout pregnancy, with a significant negative correlation with TBG levels (rs= -0.51, P0.0001), as well as with weeks of gestation (rs= -0.649, P0.0001). TSH levels did not show any correlation with gestational age. Our data corroborate the need of a precise definition of FT4 normal values during pregnancy, aiming a better laboratory evaluation of thyroid dysfunctions in this group of patients.

A introdução de ensaios imunométricos (EIM) de 2ª geração, tornaram a medida de paratormônio (PTH) sérico mais disponível, simples e rápida, aumentando sua utilização. Esses métodos, baseados em dupla identificação da molécula de PTH, mediriam supostamente a molécula intacta, bioativa, de seqüência 1-84. Recentes trabalhos mostraram que eles também medem formas com deleções amino-terminais, como a forma 7-84, que não ativam o receptor tradicional de PTH (PTH1R). Em função disto, um aspecto prático importante é a definição das formas de PTH medidas pelos EIM, sendo que estas dependem da especificidade dos anticorpos empregados. Neste trabalho, comparamos um ensaio imunofluorométrico por nós desenvolvido, que apresenta reatividade cruzada de 50% com a seqüência 7-84 do PTH, com dois ensaios comerciais de 2ª geração, que reagem 100%. Numa 1ª. comparação, 135 amostras de soro foram dosadas com o nosso ensaio e com um ensaio eletroquimioluminescente, obtendo-se uma correlação de 0,961 (P

Desde sua descrição, há mais de 40 anos, a pesquisa de anticorpos (Ac) contra antígenos (Ag) tiroideanos tem tido papel importante no diagnóstico da patologia tiroideana. A tiróide é freqüentemente acometida por doenças autoimunes, daí o interesse pela definição dos Ag tiroideanos que podem estar envolvidos no processo. O primeiro Ag reconhecido foi a tireoglobulina, seguido do fator microssomal, mais tarde identificado como a peroxidase tiroideana, o receptor de TSH e mais recentemente outros Ag como o cotransportador de sódio e iodo (sodium/iodide symporter, NIS). As metodologias evoluíram dos ensaios iniciais por hemaglutinação até o emprego atual de Ag recombinantes, marcadores alternativos e células transfectadas. Atualmente as indicações clínicas da pesquisa de Ac anti-tiroideanos são bem definidas, sendo o de maior aplicação a pesquisa de Ac anti-peroxidase, que é o que apresenta maior especificidade e sensibilidade para a definição da presença de doença autoimune tiroideana. A pesquisa de Ac anti-tireoglobulina é fundamental como complemento da dosagem de tireoglobulina no acompanhamento de pacientes com carcinoma diferenciado de tiróide. Já a pesquisa de Ac anti-receptor de TSH tem indicação precisa na definição da presença de doença de Graves. As indicações de pesquisa de Ac contra outros Ag tiroideanos não têm, atualmente, indicações comprovadas. A contínua evolução metodológica deverá aumentar ainda mais as indicações e utilidades da pesquisa de Ac contra Ag tiroideanos. Since the first publication, more than 40 years ago, laboratory tests for the presence of antibodies (Ab) to thyroid antigens (Ag) have played a pivotal position in the diagnosis of thyroid diseases. Thyroid is a common target for autoimmune diseases, hence the interest in the definition of the thyroid Ag that could be involved in the process. The first Ag to be recognized was thyroglobulin, followed by the microsomal Ag, later identified with thyroid peroxidase, the TSH receptor and, more recently, other Ag like the sodium/iodide symporter (NIS). The methodologies employed evolved from the initial hemaglutination assays, to the present use of recombinant Ag, alternative labels and transfected cells. Today the clinical uses of a test to detect the presence of Ab against thyroid Ag are very well defined. The most useful test is the detection of anti-peroxidase Ab, the test with greatest sensitivity and specificity for the presence of autoimmune thyroid diseases. The anti-thyroglobulin test is mandatory as a complement for the measurement of thyroglobulin in the follow-up of patients with differentiated thyroid cancers. The anti-TSH receptor test has its main use in the definition of the presence of Graves disease. Tests for the presence of Ab against other thyroid Ag have no clear indication at the moment. The continuous methodological developments will certainly increase the utility of tests for anti-thyroid Ab. Universidade Federal de São Paulo (UNIFESP) EPM Departamento de Medicina UNIFESP, EPM, Depto. de Medicina SciELO

O hiperparatiroidismo primário (HPP) é caracterizado pelo aumento da secreção de PTH, com conseqüente aumento da concentração sérica de cálcio. O diagnóstico é realizado pela dosagem de cálcio e PTH. A cintilografia das paratiróides é solicitada, classicamente, em pacientes com recorrência de HPP após paratiroidectomia, na tentativa de detectar glândulas patológicas ectópicas ou remanescentes. Algumas vezes este exame tem sido solicitado antes do primeiro ato cirúrgico, na tentativa de localizar as glândulas comprometidas e abreviar a duração da cirurgia; na nossa casuística, no entanto, a maioria dos exames solicitados com esta indicação resulta negativa. Comparamos os níveis séricos de cálcio e PTH nos pacientes com cintilografia das paratiróides positiva, com aqueles dos pacientes com cintilografia negativa, a fim de tentar definir níveis com índice maior de positividade na cintilografia. Foram estudados retrospectivamente 74 pacientes consecutivos submetidos à cintilografia das paratiróides. Avaliou-se a utilização dos valores mais baixos de PTH (79pg/mL) e cálcio (10mg/dL) registrados no grupo com cintilografia positiva como referência para a indicação do exame. No grupo total de pacientes, 17 (23%) apresentaram cintilografia positiva. No subgrupo com valores de PTH > ou = 79pg/mL e de cálcio > ou = 10 mg/dL a porcentagem de exames positivos foi de 49%. Concluímos que cintilografias das paratiróides realizadas antes da cirurgia de paratiroidectomia em pacientes com níveis de cálcio sérico abaixo do limite superior da normalidade ou níveis de PTH pouco aumentados são, na maioria das vezes, negativas.

O diagnóstico laboratorial de hiperparatiroidismo primário baseia-se no encontro de hipercalcemia na presença de níveis séricos elevados ou inapropriadamente normais de paratormônio (PTH). Uma vez confirmado o diagnóstico laboratorial, paratiroidectomia pode ou não ser indicada, na dependência de critérios clínicos e laboratoriais. Quando a cirurgia é indicada, diversos exames localizatórios de imagem cervicais (ultra-sonografia, tomografia, ressonância magnética, cintilografia) podem ser solicitados com o objetivo de auxiliar o cirurgião, indicando qual a localização de uma ou mais glândulas paratiróides aumentadas. Entretanto, tais exames apresentam sensibilidades variadas, na dependência quase sempre direta dos níveis séricos de PTH. Além disso, a coexistência de nódulos tiroideanos pode levar a resultados falso-positivos. Neste artigo, descrevemos três pacientes portadoras de hiperparatiroidismo primário com localização do nódulo cervical suspeito no pré-operatório. A natureza paratiroideana destes nódulos foi confirmada através da dosagem de PTH no material aspirado da punção dos respectivos nódulos cervicais High or inappropriately normal parathormone (PTH) levels in the presence of hypercalcemia are very suggestive of primary hyperparathyroidism. Once the biochemical diagnosis is confirmed, surgery may be indicated according to specific guidelines. When this is the case, several preoperative localization studies may be performed, such as ultrasonography, computerized tomography, magnetic resonance and parathyroid scintigraphy. These exams may be ordered in an attempt to help the surgeon by pointing out the precise localization of one or more enlarged parathyroid glands. However, these exams have variable sensitivities, which usually correlate with serum levels of PTH. Moreover, the coexistence of thyroid nodules may lead to false-positive observations. We herein describe three patients with primary hyperparathyroidism, whose parathyroid nature of preoperative suspicious localized cervical nodules were confirmed by PTH measurement in needle aspirates of these nodules.

Osteoporosis is a multifactorial disease with great impact on morbidity and mortality mainly in postmenopausal women. Although it is recognized that factors related to life-style and habits may influence bone mass formation leading to greater or lower bone mass, more than 85% of the variation in bone mineral density (BMD) is genetically determined. The collagen type I alpha 1 (COLIA1) gene is a possible risk factor for osteoporosis. We studied a population of 220 young women from the city of São Paulo, Brazil, with respect to BMD and its correlation with both COLIA1 genotype and clinical aspects. The distribution of COLIA1 genotype SS, Ss and ss in the population studied was 73.6, 24.1 and 2.3%, respectively. No association between these genotypes and femoral or lumbar spine BMD was detected. There was a positive association between lumbar spine BMD and weight (P

O hiperparatiroidismo primário (HPP) é uma endocrinopatia muito freqüente. A elevação do cálcio sérico é via de regra um marcador do estado de autonomia paratiroidiana, o que faz com que a hipótese de HPP seja investigada em todos os pacientes que apresentem hipercalcemia. Níveis de PTH aumentados ou inapropriadamente normais na vigência de uma hipercalcemia são fortemente sugestivos de HPP. Por outro lado, é extremamente improvável levantar uma hipótese de HPP na ausência de hipercalcemia. A dosagem de cálcio ionizado tem a vantagem de não sofrer influência dos níveis de proteína sérica. Os métodos atuais para dosagem de PTH (ensaios imunorradiométricos e imunoquimioluminométricos) são voltados para a medida da molécula intacta, mas reconhecem não só o PTH 1-84, como o fragmento 7-84. Recentemente, ensaios que medem apenas o chamado PTH bioativo (PTH 1-84) tornaram-se disponíveis comercialmente. Nos casos de hipercalcemia humoral maligna, os níveis de PTH são indetectáveis, o que facilita muito o diagnóstico diferencial com HPP na maioria dos casos. Apesar das dosagens de cálcio e de PTH serem suficientes e necessárias para o diagnóstico de HPP, outros exames complementares são úteis para a caracterização das possíveis complicações de HPP com conseqüentes implicações para a avaliação da decisão a ser tomada (indicação cirúrgica ou apenas observação e monitorização clínica e laboratorial periódica). Estes exames incluem avaliação da função renal, calciúria de 24 horas, ultrassonografia renal e de vias urinárias e densitometria óssea. Primary hyperparathyroidism (PHP) is a frequent endocrinopathy. Increased serum calcium levels may be considered as a potential marker for parathyroid autonomy and this explains why PHP should be routinely investigated in whoever presents with hypercalcemia. High or inappropriately normal PTH levels in the presence of hypercalcemia are very suggestive of PHP. On the other hand, PHP is very unlikely in the absence of hypercalcemia. Extracellular calcium concentrations may be evaluated by the measurement of total or ionized calcium, but the serum protein levels do not affect ionized calcium level. Regarding PTH, the current methods available detect the intact molecule of PTH (immunoradiometric and immunochemiluminescent assays), including PTH 1-84 and 7-84. Recently, assays that only detect the so-called bioactive PTH (1-84 PTH) are available. PTH levels are undetectable in humoral hypercalcemia of malignancy. In short, measuring serum calcium and PTH should be enough for the diagnosis of PHP. To further evaluate a patient with PHP and its potential bone and renal complications, one can order other exams such as evaluation of renal function, daily urinary calcium excretion, renal ultrassonography and bone densitometry. These exams may be useful to help the physician decide whether surgery should be indicated or not. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Medicina Fleury - Centro de Medicina Diagnóstica UNIFESP, EPM, Depto. de Medicina SciELO

A maioria dos hormônios polipeptídicos e mesmo o cálcio extracelular atuam em suas células-alvo através de receptores acoplados à proteína G (GPCRs). Nos últimos anos, tem sido freqüente a identificação e associação causal de mutações em proteínas G e em GPCRs com diversas endocrinopatias, como diabetes insipidus nefrogênico, hipotiroidismo familiar, puberdade precoce familiar no sexo masculino e nódulos tiroidianos hiperfuncionantes. Nesta revisão, abordamos aspectos referentes ao mecanismo de transdução do sinal acoplado à proteína G, e descrevemos como mutações em GPCRs podem levar a algumas doenças endócrinas. Finalmente, comentamos a respeito das implicações diagnósticas e terapêuticas associadas com o maior conhecimento dos GPCRs. The majority of polypeptide hormones and even extracellular calcium signal their target cells through G protein-coupled receptors (GPCRs). Recently, many mutations have been both identified and associated with several endocrine disorders, such as nephrogenic diabetes insipidus, familial hypothyroidism, familial male precocious puberty and sporadic hyperfunctional thyroid nodules. In this review, the G-protein coupled signal transduction mechanism is described. Moreover, the mechanism through which GPCRs’ mutations lead to endocrine disease is reviewed. Finally, we will comment on implications for diagnosis and treatment related to increasing research on GPCRs.

Conditions and artifacts such as aortic calcification, osteophytes, hip prostheses, and metallic objects can mislead the results of dual X-ray absorptiometry (DXA) scanning of the spine and hip. Gluteal silicon implants increasingly are being used for aesthetic purposes by women in Brazil, some of whom are at an age of high risk for the development of postmenopausal osteoporosis. We herein report a case of a woman whose hip bone mineral density by DXA clearly increased after the placement of bilateral gluteal silicon implants. This case demonstrates the importance of inquiring about the presence of this artifact to avoid unnecessary evaluation of hip bone densitometry in these situations.

Dear Editor, Osteoporosis-pseudoglioma syndrome (OPPG) is an autosomal recessive disorder characterized by low bone mass and ocular globe alterations, with frequent fractures as a consequence of high skeletal fragility and severe visual deficiency [1]. Recently, Gong et al. identified mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) that cause OPPG [2]. The LRP5 gene is located on the long arm of chromosome 11 at 11q13.4, has 23 exons, and encodes a transmembrane protein with 1,615 amino acids. This protein is a member of the low-density lipoprotein receptor (LDLR) family, the members of which have very well conserved characteristics. We had the opportunity to follow-up two brothers with clinical characteristics of OPPG, and we decided to investigate the LRP5 gene to identify any mutation that could explain the clinical features of low bone mass, fractures, and blindness. The older brother came to the hospital when he was 12 years old, (53 kg; 157 cm). At that time, lumbar bone mineral density (BMD, Hologic 4,500 A) was 0.512 g/cm (Z score −3.99). He was born blind, had a normal development until the age of 7 years, when he had lumbar pain due to the fracture of a vertebral body. At the age of 11, pain in the left leg led to the diagnosis of a tibial fracture. One month later, the same occurred in the right tibia and 2 months after that, a fracture in the right femur was detected, and he was referred to our hospital. The younger brother was 4 years old at that time and was born blind. At 2.5 years, he had a fracture of the right femur after a small fall. He was eutrophic (13 kg and 97 cm), with a lumbar BMD of 0.277 g/cm2 (Z score −5.4). Both of them had normal biochemical and hormonal parameters. Their parents were consanguineous, had normal BMD and no history of fractures or blindness, and there were no similar cases in the family. The 23 exons were analyzed and we identified an LPR5 missense mutation in the third codon of exon 8, in which an asparagine is replaced by isoleucine (N531I) in two siblings with OPPG and their consanguineous parents. The patients were found to be homozygous for this mutation, while their parents are heterozygous. This amino acid is located at the second propeller domain (YWTD repeat) in the extracellular domain of the receptor. Fifty normal participants underwent analysis of this exon, and the mutation was not present in any of them, but a polymorphism C→T (rs545382 NCBI, F549F) was found at a frequency of 1:5. According to Sidow’s program [3] of multivariate analysis of protein polymorphism (MAPP), we observed that the N531I mutant scored higher (yielding a bad amino acid substitution) and this mutation is located in the group of deleterious variants because of its high degree of evolutionary conservation. Based on these facts, we believe that this mutation is responsible for the clinical features presented in our patients and thereby define a novel mutation that causes OPPG in humans. Osteoporos Int DOI 10.1007/s00198-007-0360-x

Fractures are the feared consequences of osteoporosis and fractures of the proximal femur (FPF) are those that involve the highest morbidity and mortality. Thus far, evaluation of bone mineral density (BMD) is the best way to determine the risk of fracture. Genetic inheritance, in turn, is one of the major determinants of BMD. A correlation between different genotypes of the vitamin D receptor (VDR) and BMD has been recently reported. On this basis, we decided to determine the importance of the determination of VDR genotype in the presence of an osteoporotic FPF in a Brazilian population. We studied three groups: group I consisted of 73 elderly subjects older than 65 years (78.5 ± 7.2 years) hospitalized for nonpathological FPF; group II consisted of 50 individuals older than 65 years (72.9 ± 5.2 years) without FPF and group III consisted of 98 young normal Brazilian individuals aged 32.6 ± 6.6 years (mean ± SD). Analysis of VDR gene polymorphism by restriction fragment length polymorphism (RFLP) was performed by PCR amplification followed by BsmI digestion of DNA isolated from peripheral leukocytes. The genotype distribution in group I was 20.5% BB, 42.5% Bb and 37% bb and did not differ significantly from the values obtained for group II (16% BB, 36% Bb and 48% bb) or for group III (10.2% BB, 47.6% Bb and 41.8% bb). No differences in genotype distribution were observed between sexes or between the young and elderly groups. We conclude that determination of VDR polymorphism is of no practical use for the prediction of FPF. Other nongenetic factors probably start to affect bone mass, the risk to fall and consequently the occurrence of osteoporotic fractures with advancing age. A01 Universidade Federal de São Paulo (UNIFESP) Hospital do Servidor Público Estadual de São Paulo UNIFESP, EPM, São Paulo SciELO

IN THE CLINICAL SETTING, assessment of insulin resistance (IR) can be made without any laboratory test, but by evaluating data such as weight or BMI, among others. However, in the last few years laboratories have been asked to provide direct or indirect measures of IR. Homeostatic model assessment (HOMA-IR) is a simple and inexpensive technique to evaluate IR from basal (fasting) glucose and insulin or C-peptide concentrations, validated against a variety of physiological methods (1-4). To validate the potential use of HOMA-IR values in clinical practice, it is important to establish its distribution in a sample of normoglycemic individuals from a population with the same genetic background (2). In this regard, we aim to describe the distribution of HOMA-IR values in a large sample of Brazilian population. We analyzed retrospectively fasting insulin and glucose levels in 1,898 Brazilian adults (25% males, age range 18-90 years). All had fasting glucose 30 (n= 391) (table 1). A recent publication in a group of 312 non-obese, normoglicemic Brazilian subjects found a mean HOMA-IR of 1.7, and a threshold value for insulin resistance of 2.71 (3). The use of HOMA –IR to quantify insulin sensitivity can be helpful in clinical practice for comparisons of insulin sensitivity, gathering of longitudinal data in subjects at risk for development of abnormal glucose tolerance. Also, HOMA –IR can be used to assess longitudinal changes of IR in patients with diabetes in order to examine the natural history of the disease and to assess the effects of treatment, as demonstrated for example in the U.K. Prospective Diabetes Study (UKPDS) (5). Our results can be useful as a reference for further Brazilian studies using HOMA-IR values as a measure of IR in this particular population. carta ao editor Distribution of HOMA-IR in Brazilian Subjects with Different Body Mass Indexes

Interference in immunoassays from endogenous antibodies directed against peptide hormones is a well-documented phenomenon. It is known to occur for insulin, growth hormone, and especially prolactin, being responsible for most cases of “macroprolactin” (1)(2)(3). However, interference is rare in assays for pituitary glycoprotein hormones, being described only for thyroid-stimulating hormone (4)(5). To date, it has not been described for luteinizing hormone (LH). We present the case of a female patient, 23 years of age, with a diagnosis of congenital adrenal hyperplasia …

Given that the "gold standard" method for evaluating insulin sensitivity in vivo (hyperinsulinemic euglycemic glucose clamp technique) cannot be routinely applied because of technical reasons, simple methods and indexes were developed and are currently available to assess insulin sensitivity in vivo. Quantitative insulin sensitivity check index (QUICKI) has recently been described and is able to accurately estimate insulin sensitivity from a fasting blood sample. We demonstrated that fasting insulin levels strongly inversely correlated with QUICKI in three different groups: 215 healthy nondiabetic nonobese subjects, 62 nondiabetic obese subjects, and 44 patients with glucose intolerance or type 2 diabetes mellitus. Fasting insulin measurement is a simple way of assessing insulin sensitivity in obese and nonobese humans, with or without glucose intolerance or type 2 diabetes mellitus.