Influence of the TAS2R38 Gene Single Nucleotide Polymorphisms in Metabolism and Anthropometry in Thyroid Dysfunction.

The gene TAS2R38 single nucleotide polymorphisms (SNPs-P49A, A262V and V296I) can condition bitter tasting by PAV (proline-alanine-valine) and non-bitter-tasting by AVI (alanine-valine-isoleucine) homozygosity. We evaluated this polymorphisms association with thyroid function, metabolism and anthropometry parameters determined by: Endpoint analysis (SNPs); DXA (fat mass-%, total fat mass-kg, lean mass-kg); Standard methods (lipid metabolism parameters, HbA1c-%, glycemia-mg/dL, insulinemia-µIU/mL, HOMA-IR, uricemia-mg/dL, calcemia-mg/dL and BMI-kg/m2); ELISA (leptinemia-ng/mL); Spectrophotometry (Angiotensin Converting Enzyme activity-UI/L). Statistics: SPSS program; OR [IC95%]; p < 0.05. Sample: 114 hypothyroid, 49 hyperthyroid, and 179 controls. An association between A262V-valine-valine and hypothyroidism/hyperthyroidism was verified (OR = 2.841; IC95% [1.726-4.676]), p < 0.001/OR = 8.915; IC95% [4.286-18.543]), p < 0.001). Protector effect from thyroid dysfunction: A262V-alanine-valine (OR = 0.467; IC95% [0.289-0.757], p = 0.002/OR = 0.132; IC95% [0.056-0.309], p < 0.001) and PAV (OR = 0.456; IC95% [0.282-0.737], p = 0.001/OR = 0.101; IC95% [0.041-0.250], p < 0.001). Higher parameter values associated with genotypes were: fat-mass-% (V296I-valine-isoleucine), lean-mass (P49A-proline-proline; PVI), leptin (AVI), HbA1c (A262V-alanine-valine) and lower values in lean-Mass (AVI; PVV), leptin (A262V-alanine-alanine), HbA1c (PVV), uricemia (V296I-valine-isoleucine), glycemia (A262V-alanine-alanine; AAV) and plasma triglycerides (PVV). In conclusion, TAS2R38 influences thyroid function, body composition and metabolism. Bitter taste perception (PAV) and the genotype A262V-alanine-valine can protect from thyroid dysfunction. AVV, PVV and genotype A262V-valine-valine may confer higher predisposition for thyroid dysfunction, particularly PVV for hyperthyroidism.

Differences in the genotype frequencies of genes related to blood pressure regulation - a comparative study between South-West Europe and Peri-equatorial Africa.

Background: Since the emergence of the genus Homo, hominids have occupied a wide variety of environments, facing different selective pressures. Objectives: The aim this study is to compare genotype frequencies between South-West Europe and Peri-equatorial Africa in genes potentially modulators of blood pressure. Methods: The analyzed sample consisted of 325 individuals from Portugal and 226 individuals from Africa (48 from Mozambique and 178 from São Tomé and Príncipe). The following genetic variants were analyzed: intron 4 VNTR in eNOS, rs1050829 in G6PD, -3.7kb α-thalassemic deletion in HBA, rs1800457 in CYB5R3, Hp 1/2 genotype/phenotype in Hp and intron 16 I/D in ACE. Results: Frequencies of genotypes with the 4a allele in eNOS (p<0.001), the G allele in G6PD (p<0.001), the α-3.7 kb in HBA (p <0.001), the C allele in the CYB5R3 (p<0.001) were higher in Peri-equatorial Africa. The Hp 1.1 genotype of Hp has a higher frequency in Peri-equatorial Africa (p=0.002). ACE shows no significant differences. Conclusion: Results show differences in five genetic variants. Conditions of extreme heat and humidity, characteristic of Peri-equatorial Africa, have been associated with increased sodium loss. This study suggests that selected compensatory mechanisms printed in the genome, are nowadays risk factors for hypertension in Peri-equatorial Africa.

Vitamin D supplementation guidelines.

Research carried out during the past two-decades extended the understanding of actions of vitamin D, from regulating calcium and phosphate absorption and bone metabolism to many pleiotropic actions in organs and tissues in the body. Most observational and ecological studies report association of higher serum 25-hydroxyvitamin D [25(OH)D] concentrations with improved outcomes for several chronic, communicable and non-communicable diseases. Consequently, numerous agencies and scientific organizations have developed recommendations for vitamin D supplementation and guidance on optimal serum 25(OH)D concentrations. The bone-centric guidelines recommend a target 25(OH)D concentration of 20ng/mL (50nmol/L), and age-dependent daily vitamin D doses of 400-800IU. The guidelines focused on pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30ng/mL (75nmol/L), and age-, body weight-, disease-status, and ethnicity dependent vitamin D doses ranging between 400 and 2000IU/day. The wise and balanced choice of the recommendations to follow depends on one's individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice. While natural sources of vitamin D can raise 25(OH)D concentrations, relative to dietary preferences and latitude of residence, in the context of general population, these sources are regarded ineffective to maintain the year-round 25(OH)D concentrations in the range of 30-50ng/mL (75-125nmol/L). Vitamin D self-administration related adverse effects, such as hypercalcemia and hypercalciuria are rare, and usually result from taking extremely high doses of vitamin D for a prolonged time.

[Endocrinology in Portugal - Census 2016. Board of the Portuguese College of Endocrinology and Nutrition of the Portuguese Medical Association]. / A Endocrinologia em Portugal - Censo 2016. Direção do Colégio de Endocrinologia e Nutrição da Ordem dos Médicos.

INTRODUCTION: On September 2016, the Board of the College of Endocrinology and Nutrition of the Portuguese Medical Association carried out a national survey, about all Endocrinology, Diabetes and Metabolism Departments of the public hospitals included in the Portuguese National Health Service and a simplified version of this survey was sent to all endocrinologists working in Portugal and registered with the Portuguese Medical Association. MATERIAL AND METHODS: Data related to organizational and human resources were collected, reporting the situation by the end of year 2015. The census registered 107 individuals and 27 Departments. RESULTS: The ratio of endocrinologists-population was 1.4, much lower than in the other European countries (varies between 2 to 4), resulting in alarming shortages of services in some areas of Portugal and in worse quality indicators. DISCUSSION: These data suggest that actions should be taken to increase the number of endocrinologists and departments in the country. CONCLUSION: In recent years, the number of residents has significantly increased, which will make it possible to correct this situation.

Introdução: A Direção do Colégio de Endocrinologia e Nutrição da Ordem dos Médicos realizou um inquérito nacional em setembro de 2016, a todos os serviços de Endocrinologia, Diabetes e Metabolismo dos hospitais do Serviço Nacional de Saúde e uma versão simplificada do mesmo foi enviada a todos os endocrinologistas a trabalhar em Portugal e inscritos no colégio. Material e Métodos: O censo inclui dados organizacionais e de recursos humanos relativos ao fim do ano de 2015. Registou 107 respostas individuais e 27 serviços. Resultados: O ratio de endocrinologistas por 100 000 habitantes era de 1,4, muito inferior a outros países europeus (varia de 2 a 4), que resulta numa carência grave de serviços em algumas zonas do País e em piores indicadores de qualidade. Discussão: Estes dados indicam que devem ser implementadas medidas para aumentar o número de endocrinologistas e serviços em Portugal. Conclusão: Nos últimos anos, o número de internos tem vindo a aumentar, o que vai permitir melhorar esta situação.

Hypogonadotropic hypogonadism in human immunodeficiency virus-infected men: uncommonly low testosterone levels.

Hypogonadotropic hypogonadism (HH) is common and occurs prematurely in HIV-infected men. However, HH with very low testosterone has not been described. Three men with normal pubertal development and HIV1 diagnosis at the ages of 22, 34 and 35 years. All complained of decreased libido, anejaculation and erectile dysfunction thirteen years, six months and one year after HIV diagnosis, respectively. Two had depressive syndrome and two were treated with antiretroviral therapy. Laboratory tests revealed isolated HH in all. Sellar and head CT scans were normal and all had normal CD4 count. They started testosterone replacement therapy, with symptoms improvement. Causes of HH in HIV-infected men include undernutrition, severe illness, drugs, pituitary dysfunction and comorbidities. Despite having none of these conditions (except two that were treated with low-dose psychotropics), our patients had HH with uncommonly low testosterone. This suggests that a different mechanism contributes to severe HH in HIV-infected men. LEARNING POINTS: The pathogenesis of hypogonadotropic hypogonadism in HIV-infected men is multifactorial and androgen deficiency is more often a consequence of secondary hypogonadism than primary hypogonadism.Causes of hypogonadotropic hypogonadism in HIV-infected men include undernutrition, severe illness, drugs (psychotropics, opiates, megestrol acetate or steroids), pituitary dysfunction (tumor, hyperprolactinemia), an AIDS-related lesion (very rarely) and comorbid conditions, such as antibody to hepatitis C virus seropositivity and injection drug use.Highly active antiretroviral therapy (HAART), particularly protease inhibitor therapy has been associated with sexual dysfunction in men, but the causal nature of this relation has not been clearly established.Hypogonadotropic hypogonadism with uncommonly low testosterone levels are not usually associated with the conditions referred and this suggests that a different mechanism could contribute to severe hypogonadotropic hypogonadism in HIV-infected men.Screening for hypogonadism in all HIV-infected men might help to understand its etiology.

The main autoimmune and nonautoimmune etiologies of endogenous hyperthyroidism do not seem to influence the increased prevalence of morphometric vertebral fractures and osteoporosis in Portuguese men.

OBJECTIVES: The purpose of this study was to evaluate the effects of hyperthyroidism and their etiology on bone mineral density (BMD), on body soft tissue composition, on the prevalence of vertebral fractures detected by vertebral fracture assessment (VFA) and on the trabecular bone score (TBS). METHODS: From an initial population of 119 Portuguese men (78 with hyperthyroidism [HT]+ 41 controls [CTs]) admitted to the Endocrinology Department we selected 41 men aged over 50 with clinical hyperthyroidism to participate; each one was matched by age and height with a control person. BMD (g/cm2) at the lumbar spine, hip, radius 33% and whole body and the total body masses (kg) were studied by dual-energy X-ray absorptiometry (DXA). VFA with Genant semiquantitative method was used to detect fractures. The TBS was obtained from lumbar spine DXA images. No patient had been treated previously for hyperthyroidism or osteoporosis. Adequate statistical tests were used. RESULTS: In the hyperthyroidism group, total lean mass (CT 58.16 ± 7.7 vs. HT 52.3 ± 5.7, P = 0.03) and distal radius BMD (CT 0.769 ± 0.05 vs. HT 0.722 ± 0.08, P = 0.005) were lower; there was a significantly higher prevalence of osteoporosis (CT 9.7% vs. HT 29.3%, P = 0.015) and vertebral fractures (CT 2.4% vs. HT 24.4%, P = 0.007). TBS was similar in both groups (CT 1.328 ± 0.11 vs. HT 1.356 ± 0.11, P = not significant). Comparing patients with Graves' disease with patients with toxic goiter, there were no differences regarding BMD, BMD qualification, prevalence of fractures and TBS and just total lean mass was significantly lower in patients with Graves' disease. CONCLUSIONS: These results suggest that in a group of hyperthyroid men aged over 50 there are significant decreases in cortical bone BMD and lean mass and a higher prevalence of osteoporosis and silent vertebral fractures, but the etiology of the hyperthyroidism does not seem to influence it. Besides the antithyroid drugs, some patients may benefit from bone-directed treatments.

Multidisciplinary Portuguese recommendations on DXA request and indication to treat in the prevention of fragility fractures.

OBJECTIVE: To establish Portuguese recommendations regarding the indication to perform DXA and to initiate medication aimed at the prevention of fragility fractures. METHODS: A multidisciplinary panel, representing the full spectrum of medical specialties and patient associations devoted to osteoporosis, as well as national experts in this field and in health economics, was gathered to developed recommendations based on available evidence and expert consensus. Recently obtained data on the Portuguese epidemiologic, economic and quality-of-life aspects of fragility fractures were used to support decisions. RESULTS: 10 recommendations were developed covering the issues of whom to investigate with DXA and whom to treat with antifracture medications. Thresholds for assessment and intervention are based on the cost-effectiveness analysis of interventions at different thresholds of ten-year probability of osteoporotic fracture, calculated with the Portuguese version of FRAX® (FRAX®Port), and taking into account Portuguese epidemiologic and economic data. Limitations of FRAX® are highlighted and guidance for appropriate adjustment is provided, when possible. CONCLUSIONS: Cost-effectiveness thresholds for DXA examination and drug intervention aiming at fragility fracture prevention are now provided for the Portuguese population. These are practical, based on national epidemiological and economic data, evidence-based and supported by a wide scope multidisciplinary panel of experts and scientific societies. Implementation of these recommendations holds great promise in assuring the most effective use of health resources in the prevention of osteoporotic fractures in Portugal.

Assessing quality of life in severe obesity: development and psychometric properties of the ORWELL-R.

PURPOSE: Several health-related quality-of-life (HRQoL) dimensions are affected by obesity. Our goal was to characterize the psychometric properties of the ORWELL-R, a new obesity-related quality-of-life instrument for assessing the "individual experience of overweightness". METHODS: This psychometric assessment included two different samples: one multicenter clinical sample, used for assessing internal consistency, construct validity and temporal reliability; and a community sample (collected through a cross-sectional mailing survey design), used for additional construct validity assessment and model fit confirmation. RESULTS: Overall, 946 persons participated (188 from the clinical sample; 758 from community sample). An alpha coefficient of 0.925 (clinical sample) and 0.934 (community sample) was found. Three subscales were identified (53.2 % of variance): Body environment experience (alpha = 0.875), Illness perception and distress (alpha = 0.864), Physical symptoms (alpha = 0.674). Adequate test-retest reliability has been confirmed (ICC: 0.78 for the overall score). ORWELL-R scores were worse in the clinical sample. Worst HRQoL, as measured by higher ORWELL-R scores, was associated with BMI increases. ORWELL-R scores were associated with IWQOL-Lite and lower scores in happiness. CONCLUSIONS: ORWELL-R shows good internal consistency and adequate test-retest reliability. Good construct validity was also observed (for convergent and discriminant validity) and confirmed through confirmatory factor analysis (in both clinical and community samples). Presented data sustain ORWELL-R as a reliable and useful instrument to assess obesity-related QoL, in both research and clinical contexts.

Valor clínico del puntaje óseo trabecular calculado a partir de la absorciometría de rayos X de energía dual de columna / Clinical importance of the Trabecular Bone Score obtained from spine dual-energy x-ray absorptiometry

Intrínsecamente, se acepta el hecho de que definir a la osteoporosis solamente sobre la base de la densidad mineral ósea proyectada (DMO mediante DXA) ha llegado a su límite. De hecho, el aspecto multifactorial de esta enfermedad hace que la definición actual de osteoporosis evolucione hacia un modelo de riesgo complejo basado en el Factor de Riesgo Clínico (FRC) y la DMO. El puntaje óseo trabecular (TBS, Trabecular Bone Score) es una nueva medición de escala de grises que se basa en el uso de variogramas experimentales sobre imágenes en proyección 2D, y que permite diferenciar entre dos microarquitecturas tridimensionales (3D) que presentan la misma densidad ósea pero diferentes características trabeculares. El TBS mide la tasa promedio de variación local en escala de grises sobre imágenes de proyección 2D. Este parámetro se obtiene luego del re-análisis de un examen de DXA, y puede compararse con la DMO dado que ambos evalúan la misma región ósea. El valor agregado del TBS respecto de la densitometría mineral ósea para la evaluación del riesgo de fracturas ha sido documentado en estudios transversales, prospectivos y longitudinales. De hecho, se ha hallado que el TBS: 1) es más bajo en mujeres posmenopáusicas con una fractura osteoporótica previa, comparado con mujeres sin fractura pareadas por edad y DMO; 2) brinda un aumento incremental en el odds ratio para fractura de columna cuando se combina con la DMO de columna; 3) es más bajo en mujeres con fracturas (comparado con aquellas sin fracturas), independientemente de si su DMO reúne los criterios para osteoporosis u osteopenia; 4) predice fracturas en forma prospectiva, tal como lo hace la DMO; 5) rescata alrededor de 1/3 de las fracturas clasificadas de manera errónea según la definición de DMO de la OMS para osteoporosis aislada; y 6) se comporta de manera diferente de acuerdo con el tipo de terapia ósea implementada. El objetivo de esta breve revisión consiste en brindar información acerca de los ensayos clínicos actuales referentes al TBS, además de posicionar a este parámetro en la práctica clínica como complemento de la DMO en vista de su actual validación.

Intrinsically it is accepted that defining osteoporosis on the sole basis of projected bone mineral density (BMD by DXA) has reached its limit. Indeed, the multifactorial aspect of this disease means that the current definition of osteoporosis is evolving towards a complex risk model based on Clinical Risk Factor (CRF) and BMD. The Trabecular Bone Score (TBS) is a novel grey-level texture measurement that is based on the use of experimental variograms of 2D projection images, and is able to differentiate between two 3-dimensional (3D) micro-architectures that exhibit the same bone density, but different trabecular characteristics. TBS measures the mean rate of local variation of grey levels in 2D projection images. The TBS is obtained after re-analysis of a DXA exam, and can be compared with BMD, since both evaluate the same region of bone. The added value of the TBS in bone mineral densitometry for fracture risk assessment has been documented in cross-sectional, prospective and longitudinal studies. Indeed, TBS has been found to: 1) be lower in post-menopausal women with a past osteoporotic fracture compared with age- and BMD-matched women without fracture; 2) give an incremental increase in the odds ratio for spine fracture when combined with spine BMD; 3) be lower in women with (versus without) fractures, irrespective of whether their BMD met the criteria for osteoporosis or osteopenia; 4) prospectively predict facture as well as spine BMD; 5) recapture around 1/3 of mis-classified fractures according to the BMD WHO definition of osteoporosis alone, and 6) react differently according to the type of bone therapy. The aim of this short review is to report the current clinical studies as well as to position TBS in clinical routine to complement BMD in the light of its current validation.

Thyroid nodule: first manifestation of chronic lymphocytic leukaemia.

The presence of chronic lymphocytic leukaemia (CLL) cells in the thyroid gland is most likely due to a secondary involvement by a systemic disease. The reported incidence of CLL involving the thyroid is extremely low, representing about 3-4% of all thyroid lymphoproliferative neoplasm. We report a rare case of CLL presenting initially in the thyroid gland. Systemic disease was detected as a result of thyroid investigation. An 85 years old woman, with multinodular goiter without adenophaties, was referred to our department, carrying a fine needle aspiration biopsy (FNAB) report of a private institution referring "lymphoid monomorphic proliferation" and suggesting a "Core-needle biopsy" for further investigation. She was euthyroid (TSH-0.5 uU/mL (0.4-4.0), thyroid antibodies negative, including TRab). The patient denied systemic symptoms and at physical examination there were no adenophaties or organomegalies. FNAB analysis was repeated. Although the patient denied constitutional symptoms and there were no relevant findings in physical examination, technetium 99m thyroid gamagraphy (GG) and blood count were additionally asked. FNAB analysis concluded lymphocytic tiroiditis, but thyroid GG revelled global hypocaptation and blood count showed 173.4 x 109 leukocyte/L with 94% lymphocyte. An ecoguided FNAB with flow cytometry identified thyroid infiltration by monotonous population of blasts with phenotype consistent with CLL/malignancy of mature B-cells. CLL/malignancy of mature B-cells was also detected in peripheral blood analysis, suggesting systemic disease with secondary thyroid involvement. The patient started chemotherapy with rituximab and chlorambucil with good response. Pos-treatment GG revelled "Increased levels of uptake in the middle third of the right lower lobe, with low uptake of the remaining parenchyma". In conclusion, good communication with the pathologist can improve diagnostic accuracy and dictate appropriate therapy. The use of techniques such as flow cytometry, immunoglobulin gene rearrangements, and immunohistochemistry has improved diagnostic accuracy and obviated more invasive procedures, such as core needle or open surgery biopsy. Apart from chemotherapy, immunochemotherapy with anti-CD20 and anti-CD52 monoclonal antibodies can be used in the treatment of CLL.

Thyroid nodule: first manifestation of chronic lymphocytic leukaemia

The presence of chronic lymphocytic leukaemia (CLL) cells in the thyroid gland is most likely due to a secondary involvement by a systemic disease. The reported incidence of CLL involving the thyroid is extremely low, representing about 3–4% of all thyroid lymphoproliferative neoplasm. We report a rare case of CLL presenting initially in the thyroid gland. Systemic disease was detected as a result of thyroid investigation. An 85 years old woman, with multinodular goiter without adenophaties, was referred to our department, carrying a fine needle aspiration biopsy (FNAB) report of a private institution referring “lymphoid monomorphic proliferation” and suggesting a “Core-needle biopsy” for further investigation. She was euthyroid (TSH–0.5 uU/mL (0.4-4.0), thyroid antibodies negative, including TRab). The patient denied systemic symptoms and at physical examination there were no adenophaties or organomegalies. FNAB analysis was repeated. Although the patient denied constitutional symptoms and there were no relevant findings in physical examination, technetium 99m thyroid gamagraphy (GG) and blood count were additionally asked. FNAB analysis concluded lymphocytic tiroiditis, but thyroid GG revelled global hypocaptation and blood count showed 173.4 x 109 leukocyte/L with 94% lymphocyte. An ecoguided FNAB with flow cytometry identified thyroid infiltration by monotonous population of blasts with phenotype consistent with CLL/malignancy of mature B-cells. CLL/malignancy of mature B-cells was also detected in peripheral blood analysis, suggesting systemic disease with secondary thyroid involvement. The patient started chemotherapy with rituximab and chlorambucil with good response. Pos-treatment GG revelled “Increased levels of uptake in the middle third of the right lower lobe, with low uptake of the remaining parenchyma”. In conclusion, good communication with the pathologist can improve diagnostic accuracy and dictate appropriate therapy. The use of techniques such as flow cytometry, immunoglobulin gene rearrangements, and immunohistochemistry has improved diagnostic accuracy and obviated more invasive procedures, such as core needle or open surgery biopsy. Apart from chemotherapy, immunochemotherapy with anti-CD20 and anti-CD52 monoclonal antibodies can be used in the treatment of CLL.

Prevalence of silent vertebral fractures detected by vertebral fracture assessment in young Portuguese men with hyperthyroidism.

BACKGROUND: Hyperthyroidism is a risk factor for reduced bone mineral density (BMD) and osteoporotic fractures. Vertebral fracture assessment (VFA) by dual-energy X-ray absorptiometry (DXA) is a radiological method of visualization of the spine, which enables patient comfort and reduced radiation exposure. OBJECTIVES: This study was carried out to evaluate BMD and the prevalence of silent vertebral fractures in young men with hyperthyroidism. DESIGN: We conducted a cross-sectional study in a group of Portuguese men aged up to 50 years and matched in hyperthyroidism (n=24) and control (n=24) groups. MATERIALS AND METHODS: A group of 48 Portuguese men aged up to 50 years was divided and matched in hyperthyroidism (n=24) and control (n=24) groups. BMD (g/cm(2)) at L1-L4, hip, radius 33%, and whole body as well as the total body masses (kg) were studied by DXA. VFA was used to detect fractures and those were classified by Genant's semiquantitative method. No patient had previously been treated for hyperthyroidism, osteoporosis, or low bone mass. Adequate statistical tests were used. RESULTS: The mean age, height, and total fat mass were similar in both groups (P≥0.05). The total lean body mass and the mean BMD at lumbar spine, hip, and whole body were significantly decreased in the hyperthyroidism group. In this group, there was also a trend for an increased prevalence of reduced BMD/osteoporosis and osteoporotic vertebral fractures. CONCLUSIONS: The results obtained using VFA technology (confirmed by X-ray) suggest that the BMD changes in young men with nontreated hyperthyroidism may lead to the development of osteoporosis and vertebral fractures. This supports the pertinence of using VFA in the routine of osteoporosis assessment to detect silent fractures precociously and consider early treatment.

A case of thyroid hormone resistance: a rare mutation / Caso de resistência aos hormônios tireóideos: mutação rara

Reduced sensitivity to thyroid hormones (RSTH) is a rare disease that affects about 3,000 individuals, belonging to about 1,000 families. It results from reduced intracellular action of thyroid hormones (TH) genetically determined and manifests as persistent hyperthyroxinemia with non-suppressed thyroid-stimulating hormone (TSH). We describe a 67-years old, Caucasian woman, with past history of subtotal thyroidectomy due to diffuse goiter, who presents with a recurrence of goiter. Although she is clinically euthyroid, laboratory evaluation shows persistent hyperthyroxinemia with non-suppressed TSH. Response to thyrotropin releasing hormone (TRH) test was normal and TSH concentrations were not suppressed during oral administration of suprafisiologic doses of levothyroxine (L-T4). Peripheral blood DNA was extracted from the patient and a mutation was found localized in cluster one, at codon 346 of the ligand binding domain of the THRB gene. The patient’s son underwent thyroid function testing (TFT) and genetic study, both negative, suggesting a sporadic mutation. RSTH should be considered in all hyperthyroxinemic patients who are clinically euthyroid. Mutations interfering with three major steps required for TH action on target tissues have been, so far, identified (TR-β, TR-α, MCT8, SPB2). Each mutation is associated with a distinctive syndrome. Goal of management is to maintain a normal serum TSH level and a eumetabolic state and offer appropriate genetic counselling and prenatal diagnosis. Inappropriate treatment of eumetabolic patients results in hypothyroidism and need for TH replacement.

A sensibilidade reduzida aos hormônios tiroidianos (RSTH) é uma doença rara que afeta cerca de 3.000 indivíduos em 1.000 famílias. Ela resulta de uma ação intracelular reduzida de hormônios tiroidianos (TH), é geneticamente determinada e se manifesta como hipertiroxinemia persistente com hormônio tireoestimulante (TSH) não suprimido. Descrevemos o caso de uma mulher caucasiana de 67 anos de idade com histórico de tiroidectomia subtotal por bócio difuso e que apresentou recorrência do bócio. Embora ela fosse clinicamente eutiroide, a avaliação laboratorial mostrou hipertiroxinemia persistente com TSH não suprimido. A resposta ao hormônio liberador da tireotrofina (TRH) foi normal e as concentrações de TSH não foram suprimidas durante a administração oral de doses suprafisiológicas de levotiroxina (L-T4). Foi extraído DNA de sangue periférico da paciente e encontrada uma mutação no cluster um do códon 346 do domínio de ligação do ligante do gene THRB. O filho da paciente foi submetido a um teste de função da tiroide e a um estudo genético, ambos negativos, o que sugeriu uma mutação esporádica. O RSTH deve ser considerado em todos os pacientes hipertiroxinêmicos que sejam clinicamente eutiroides. Foram identificadas, até hoje, mutações que interferem com os três passos principais necessários para a ação do TH sobre os tecidos-alvo (TR-b, TR-α, MCT8, SPB2). Cada mutação está associada com uma síndrome distinta. O objetivo do manejo é manter o nível sérico normal de TSH e um estado eumetabólico, além de se oferecer aconselhamento genético adequado e diagnóstico pré-natal. O tratamento inadequado de pacientes eumetabólicos leva ao hipotireoidismo e requer reposição de TH.

A case of thyroid hormone resistance: a rare mutation.

Reduced sensitivity to thyroid hormones (RSTH) is a rare disease that affects about 3,000 individuals, belonging to about 1,000 families. It results from reduced intracellular action of thyroid hormones (TH) genetically determined and manifests as persistent hyperthyroxinemia with non-suppressed thyroid-stimulating hormone (TSH). We describe a 67-years old, Caucasian woman, with past history of subtotal thyroidectomy due to diffuse goiter, who presents with a recurrence of goiter. Although she is clinically euthyroid, laboratory evaluation shows persistent hyperthyroxinemia with non-suppressed TSH. Response to thyrotropin releasing hormone (TRH) test was normal and TSH concentrations were not suppressed during oral administration of suprafisiologic doses of levothyroxine (L-T4). Peripheral blood DNA was extracted from the patient and a mutation was found localized in cluster one, at codon 346 of the ligand binding domain of the THRB gene. The patient's son underwent thyroid function testing (TFT) and genetic study, both negative, suggesting a sporadic mutation. RSTH should be considered in all hyperthyroxinemic patients who are clinically euthyroid. Mutations interfering with three major steps required for TH action on target tissues have been, so far, identified (TR-ß, TR-α, MCT8, SPB2). Each mutation is associated with a distinctive syndrome. Goal of management is to maintain a normal serum TSH level and a eumetabolic state and offer appropriate genetic counselling and prenatal diagnosis. Inappropriate treatment of eumetabolic patients results in hypothyroidism and need for TH replacement.

A FRAX model for the estimation of osteoporotic fracture probability in Portugal.

INTRODUCTION: The objective of this study was to develop a Portuguese version of the World Health Organization fracture risk assessment tool (FRAX®). METHODS: All cases of hip fracture occurred at or after 40 years of age were extracted from the Portuguese National Hospital Discharge Register from 2006 to 2010. Age and sex-ranked population estimates and mortality rates were obtained from National Statistics. Age- and gender stratified incidences were computed and the average of the five years under consideration was taken. Rates for other major fractures were imputed from the epidemiology of Sweden, as undertaken for most national FRAX® models. All methodological aspects and results were submitted to critical appraisal by a wide panel of national experts and representatives of the different stakeholders, including patients. RESULTS: Hip fracture incidence rates were higher in women than in men and increased with age. The lowest incidence was observed in 40-44 years group (14.1 and 4.0 per 100,000 inhabitants for men and women, respectively). The highest rate was observed among the 95-100 age-group (2,577.6 and 3,551.8/100,000 inhabitants, for men and women, respectively). The estimated ten-year probability for major osteoporotic fracture or hip fracture increased with decreasing T-score and with increasing age. CONCLUSIONS: Portugal has one of the lowest fracture incidences among European countries. The FRAX® tool has been successfully calibrated to the Portuguese population, and can now be used to estimate the ten-year risk of osteoporotic fractures in this country. All major stakeholders officially endorsed the Portuguese FRAX® model and co-authored this paper.

A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population.

Germline mutations in the WNK4 gene originate Gordon syndrome or pseudohypoaldosteronism type II, a familial form of hypertension with hyperkalemia and hypercalciuria. In order to elucidate the contribution of WNK4 genetic variants to hypertension and/or osteoporosis, we analyzed 271 control individuals and a cohort of 448 hypertensive and 372 osteoporosis patients from the Portuguese population. Ten genetic variants were detected in 4.3% of the population under study, none of which revealed any significant association to the hypertension phenotype. In contrast, a rare missense alteration within exon 17 in a highly conserved arginine residue showed a possible tendency for association to the osteoporosis group. Our data suggest that WNK4 polymorphism rs56116165 is a rare allelic variant in a candidate gene with a biological function in renal calcium homeostasis that may contribute to a genetic predisposition to osteoporosis.

Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib.

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G-protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)α), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia-related complications.

ACP1 genotype, glutathione reductase activity, and riboflavin uptake affect cardiovascular risk in the obese.

Erythrocyte acid phosphatase (ACP locus 1), also known as low-molecular-weight protein tyrosine phosphatase, has previously been associated to glycemia, dyslipidemia, and obesity. In this study, ACP1 genotype and activity were tested in 318 women aged 19 to 83 (mean, 51.74 +/- 13.44) years. ACP1 genotype was found to directly correlate to glutathione reductase activity (P < .001) and levels of low-density lipoprotein cholesterol (P = .038). Glutathione reductase activity was in turn found to correlate to a series of cardiovascular risk factors such as systolic arterial pressure (P < .001), total cholesterol levels (P = .018), and low-density lipoprotein cholesterol levels (P = .039). A possible protective effect of ACP1 genotype AA against these cardiovascular risk factors was observed in this study. Furthermore, this work hypothesizes that nutritional riboflavin uptake becomes more crucial as body mass index increases, to counteract oxidative stress and minimize cardiovascular risk. This might be especially true in ACP1 genotypes AC, BC, and CC, which might possibly show the least endogenous protection against oxidative stress.

Prevalence, severity, and risk factors for erectile dysfunction in a representative sample of 3,548 portuguese men aged 40 to 69 years attending primary healthcare centers: results of the Portuguese erectile dysfunction study.

INTRODUCTION: Many studies of the prevalence of erectile dysfunction have been conducted in several countries. This is the first Portuguese study that provides current and comparative data on the prevalence of erectile dysfunction. AIM: The main objective was to estimate the prevalence of erectile dysfunction in men aged 40 to 69 years and correlate erectile dysfunction to certain risk factors. MAIN OUTCOME MEASURES: Evaluation of erectile dysfunction was achieved using the International Index of Erectile Function (IIEF), a 15-item questionnaire that has been developed and validated as a brief and reliable self-administered scale for accessing erectile function. METHODS: The Portuguese Erectile Dysfunction Study was based on a questionnaire that included socio-demographic variables, information on lifestyle and risk factors, and the IIEF. In total, 3,548 questionnaires were administered to men aged 40 to 69 years in 50 primary healthcare centers between July 2004 and January 2005 in a combination of both self-administration and interviews. Erectile dysfunction was defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse. RESULTS: The response rate was 81.3%. The total prevalence of erectile dysfunction was 48.1% (age-adjusted). Prevalence increases with age: 29%, 50%, and 74% in men aged 40 to 49 years, 50 to 59 years, and 60 to 69 years, respectively. Severity of erectile dysfunction also increases with age: 1%, 2%, and 10% of complete erectile dysfunction in men aged 40 to 49 years, 50 to 59 years, and 60 to 69 years, respectively. CONCLUSIONS: The prevalence of erectile dysfunction is strongly related to age. There is also a correlation with the health status of participants.

A study of bone density change in patients with anorexia nervosa.

In patients with anorexia nervosa (AN) several factors combine to cause osteoporosis, and the risk of osteoporosis increases with chronicity of illness. The authors carried out a follow-up study in patients who attended the Eating Disorders department of the Hospital de Santa Maria. The average follow-up period was of 7.6 years. Fifteen patients were included. Patients answered clinical history questions and underwent neck of femur and spine densitometry. The most important variable with negative correlations to bone recovery was disease duration. A positive correlation between bone recovery and time since the first menstrual cycle post-amenorrhea was also found. However, AN is a condition in which once weight improves and menstrual cycles become regular, severe damage to bone structure is still likely to be maintained.