TSH neurosecretory dysfunction (TSH-nd) in Down syndrome (DS): low risk of progression to Hashimoto's thyroiditis / Disfunção neurossecretora de TSH na síndrome de Down: baixo risco de progressão para a tireoidite de Hashimoto

INTRODUCTION: Patients with Down syndrome (DS) often have elevated TSH (hypothalamic origin), which is called TSH neurosecretory dysfunction (TSH-nd). In these cases, there is slight elevation in TSH (5-15 µUI/mL), with normal free T4 and negative thyroid antibodies (AB). OBJECTIVE: To recognize the risk of progression to Hashimoto's thyroiditis (HT). SUBJECTS AND METHODS: We retrospectively analyzed 40 DS patients (mean age = 4.5 years), followed up for 6.8 years. RESULTS: HT was diagnosed in 9/40 patients, three early in monitoring, and six during evolution. In 31/40 patients, TSH-nd diagnosis remained unchanged over the years, with maximum TSH values ranging from 5 to 15 µUI/mL. In this group, free T4 also remained normal and AB were negative. There was a significant TSH reduction (p = 0.017), and normal TSH concentrations (< 5.0 µUI/mL) were observed in 29/31 patients, in at least one moment. No patient had TSH > 15 µUI/mL. CONCLUSION: DS patients with TSH-nd present low risk of progression to HT (10 percent for females and 6 percent for males).

INTRODUÇÃO: Pacientes com síndrome de Down (SD) geralmente apresentam TSH elevado (de origem hipotalâmica), uma desordem chamada de disfunção neurossecretora de TSH (TSH-nd). Nesses casos, há uma leve elevação do TSH (5-15 µUI/mL), com T4 livre normal e anticorpos antitireoide (AB) negativos. OBJETIVO: Reconhecer o risco de progressão para a tireoidite de Hashimoto (HT). SUJEITOS E MÉTODOS: Analisamos retrospectivamente 40 pacientes com SD (idade média = 4,5 anos), acompanhados por 6,8 anos. RESULTADOS: A HT foi diagnosticada em 9/40 pacientes, três logo no início da avaliação e seis durante a evolução. Em 31/40 dos pacientes, o diagnóstico de TSH-nd permaneceu estável durante os anos, com valores máximos de TSH variando de 5 a 15 µUI/mL. Neste grupo, o T4 livre também permaneceu normal e os AB foram negativos. Houve uma redução significativa do TSH (p = 0,017), e concentrações normais de TSH (< 5,0 µUI/mL) foram observadas em 29/31 pacientes, em pelo menos um momento. Nenhum paciente apresentou TSH > 15 µUI/mL. CONCLUSÃO: Pacientes com SD e TSH-nd apresentam baixo risco de progressão para a HT (10 por cento para o sexo feminino e 6 por cento para o sexo masculino).

[Growth hormone therapy and hypersensitivity type III reaction: a contraindication for desensitization]. / Hormônio de crescimento e hipersensibilidade por imunocomplexo (Tipo III): uma contraindicação para a dessensibilização.

Allergic reactions against GH are rare, and usually represented by the hypersensitivity type I (IgE-mediated). This type of reaction can be treated by desensitization. In this case report, we present a patient showing an allergic reaction soon after starting GH therapy mediated by immune complex (hypersensitivity type III reaction). In this condition, the attempt to perform the desensitization procedure can perpetuate immune complex deposition determining a life threatening renal and respiratory insufficiency.

Hormônio de crescimento e hipersensibilidade por imunocomplexo (Tipo III): uma contraindicação para a dessensibilização / Growth hormone therapy and hypersensitivity type III reaction: a contraindication for desensitization

As reações alérgicas ao GH são raras e usualmente representadas por reações de hipersensibilidade tipo I (IgE mediadas), passíveis de tratamento por dessensibilização. Neste relato de caso, descrevemos a presença de reação alérgica ao GH mediada por imunocomplexo (hipersensibilidade tipo III). Nesta situação, a tentativa de dessensibilização pode perpetuar a formação de imunocomplexo, cujo depósito pode determinar insuficiência renal e respiratória.

Allergic reactions against GH are rare, and usually represented by the hypersensitivity type I (IgE-mediated). This type of reaction can be treated by desensitization. In this case report, we present a patient showing an allergic reaction soon after starting GH therapy mediated by immune complex (hypersensitivity type III reaction). In this condition, the attempt to perform the desensitization procedure can perpetuate immune complex deposition determining a life threatening renal and respiratory insufficiency.

TSH neurosecretory dysfunction (TSH-nd) in Down syndrome (DS): low risk of progression to Hashimoto's thyroiditis.

INTRODUCTION: Patients with Down syndrome (DS) often have elevated TSH (hypothalamic origin), which is called TSH neurosecretory dysfunction (TSH-nd). In these cases, there is slight elevation in TSH (5-15 µUI/mL), with normal free T4 and negative thyroid antibodies (AB). OBJECTIVE: To recognize the risk of progression to Hashimoto's thyroiditis (HT). SUBJECTS AND METHODS: We retrospectively analyzed 40 DS patients (mean age = 4.5 years), followed up for 6.8 years. RESULTS: HT was diagnosed in 9/40 patients, three early in monitoring, and six during evolution. In 31/40 patients, TSH-nd diagnosis remained unchanged over the years, with maximum TSH values ranging from 5 to 15 µUI/mL. In this group, free T4 also remained normal and AB were negative. There was a significant TSH reduction (p = 0.017), and normal TSH concentrations (< 5.0 µUI/mL) were observed in 29/31 patients, in at least one moment. No patient had TSH > 15 µUI/mL. CONCLUSION: DS patients with TSH-nd present low risk of progression to HT (10% for females and 6% for males).

Prolonged physical training decreases mRNA levels of glucocorticoid receptor and inflammatory genes.

BACKGROUND/AIMS: Prolonged physical exercise induces adaptive alterations in the hypothalamic-pituitary axis, increasing cortisol metabolism, and reducing cortisol synthesis and glucocorticoid sensitivity. The mechanisms responsible for this relative glucocorticoid resistance remain unknown but may involve expression of genes encoding glucocorticoid receptor (GR) and/or inflammatory molecules of nuclear factor kappa B1 (NFkB1) signaling pathway and cytokines. This study aimed to determine the impact of prolonged physical training on the expression of genes involved in glucocorticoid action and inflammatory response. METHODS: Normal sedentary male cadets of the Brazilian Air Force Academy were submitted to 6 weeks of standardized physical training. Eighteen of 29 initially selected cadets were able to fully complete the training program. Fasting glucose, insulin and cortisol levels, cytokine concentration and the expression of genes encoding GR, NFkB1, inhibitor of NFkB1 and IkB kinase A were determined before and after the training period. RESULTS: Prolonged physical exercise reduced the basal cortisol levels and the percent cortisol reduction after dexamethasone. These findings were associated with a significant reduction in the mRNA levels of GR (6.3%), NFkB1 (63%), inhibitor of NFkB1 (25%) and IkB kinase A (46%) with concomitant reduction in cytokine concentrations (ELISA). CONCLUSIONS: Prolonged physical training decreases the glucocorticoid sensitivity and the mRNA levels of the GR gene combined with decreased mRNA of genes related to the NFkB pathway.

Impact of prolonged low-grade physical training on the in vivo glucocorticoid sensitivity and on glucocorticoid receptor-alpha mRNA levels of obese adolescents.

BACKGROUND/AIM: Healthy individuals present variable responses of the hypothalamic-pituitary-adrenal (HPA) axis induced by different patterns of physical training. The aim of this study was to evaluate whether prolonged low-grade physical training influences the HPA axis and also glucocorticoid receptor-alpha (GRalpha) mRNA levels in mononuclear cells of obese adolescents. METHODS: We studied 19 patients with BMI above the 95th percentile (male:female ratio 7:12) aged from 9.5 to 15.5 years. Patients underwent a 12-week physical exercise program. Before and after exercise, in vivo glucocorticoid sensitivity was determined by employing a very-low-dose intravenous dexamethasone suppression test, and in vitro GRalpha mRNA levels were evaluated by quantitative real-time PCR. RESULTS: After exercise there was a trend to reduce the in vivo glucocorticoid sensitivity (p = 0.071) and a significant increase in GRalpha mRNA levels (p = 0.025). CONCLUSION: For this subset of obese adolescents, prolonged low-grade physical training tended to reduce glucocorticoid sensitivity. The discrepancy of cortisol response to dexamethasone and the GRalpha mRNA measurement suggest a post-receptor phenomenon or should be related to target tissue-specific differences in glucocorticoid sensitivity. Future studies should address the adaptive GRalpha mRNA during different exercise protocols, and also the correlation of pituitary sensitivity with glucocorticoid target tissue sensitivity.

Evaluation of glucocorticoid sensitivity and its potential clinical applicability.

Glucocorticoids (GC) play an important role in physiologic and pathophysiologic adaptive responses to stress. The majority of these effects are mediated by the GC receptors (GR). GC sensitivity largely depends of the amount of available GR, and their ability to bind the GC-responsive element and/or other nuclear transcription factors, leading to modulation of the expression of GC target genes. Clinical conditions of tissue-specific GC resistance or GC hypersensitivity have been described in several diseases, such as chronic inflammatory and autoimmune conditions, and in visceral obesity, such as metabolic syndrome. Several in vivo and in vitro methods have been described, allowing the evaluation and quantitation of GC sensitivity. The recognition of these parameters has improved our comprehension of the mechanisms involved in those diseases, with potential implications for the diagnosis and therapy of such abnormalities.

A very low dose intravenous dexamethasone suppression test as an index of glucocorticoid sensitivity.

BACKGROUND/AIMS: The wide variability of responses to corticotherapy suggests a role for individual recognition of steroid sensitivity in order to customize treatment. Oral dexamethasone (DEX) administration may be hindered by the rate of its intestinal absorption and the liver first-passage effect. In this study we suggest that an intravenous very low dose DEX suppression test (VLD IV-DST) can be used as an index for glucocorticoid (GC) sensitivity. METHODS: We evaluated 87 normal subjects: 44 prepubertal children, 23 adolescents and 20 adults with a VLD IV-DST using 20 mug/m(2) of DEX (dose able to recognize GC sensitivity). Cortisol was initially measured at several time-points after DEX prompting us to establish its nadir and subsequent simplification of the test by measuring cortisol at baseline and after 120 min. RESULTS: Baseline cortisol was similar in adolescents and in adults, but lower in children. There was a spectrum of individual responses in all age groups. The percent reduction of cortisol after 120 min was different in these three age groups, with median values of 44.4% in children, 25.9% in adolescents and 61.6% in adults. CONCLUSION: This simplified VLD IV-DST using 20 mug/m(2) of DEX is useful to evaluate individual sensitivity to GC in different age groups.

Utilidade de regras booleanas aplicadas à liberação de resultados de exames hormonais e marcadores tumorais / Usefulness of Boolean rules applied on the release of hormonal and tumor markers tests results

INTRODUÇÃO: A avaliação de perfis hormonais exige, tradicionalmente, a participação de especialistas para adequada liberação setorial. A análise desses resultados através de regras booleanas é alternativa interessante para minimizar os resultados a serem avaliados manualmente. MATERIAL E MÉTODO: Avaliamos a utilização de regras booleanas construídas no programa Instrument Manager para o equipamento Architect, principalmente para mensuração de hormônios sexuais e tireoidianos, além de marcadores tumorais. O resultado da intervenção foi avaliado quanto a: a) número e facilidade de construção das regras; b) comparação cega entre liberação por patologista clínico (resultados impressos) e conjunto de regras em 940 testes consecutivos. RESULTADOS: A criação das regras se revelou tarefa complexa e trabalhosa, especialmente pela existência de perfis hormonais com diversos modos de solicitação dos testes. Foram necessárias 153 regras booleanas (do tipo se...então) em uma ordem específica. Essas regras concordaram com o especialista em 97,9 por cento dos casos (920 testes). O conjunto de regras reteve 25 casos (2,7 por cento) e o patologista clínico, apenas nove. Nos 20 casos discordantes, as regras deixaram de reter apenas dois casos, sendo um da fração beta da gonadotrofina coriônica humana (beta-hCG) em homens (que implicou a criação de nova regra) e um caso de perfil tireoidiano completo sem hormônio tireoestimulante (TSH) (o patologista clínico optou por confirmar o pedido médico). CONCLUSÃO: A criação de conjunto eficiente de regras booleanas é tarefa complexa que necessita de conhecimentos técnicos e de lógica, mas que permite a otimização do funcionamento do laboratório. Obtivemos excelente concordância entre o conjunto de regras criado e a liberação manual de patologista clínico, garantindo a segurança, a velocidade e o menor custo do sistema.

BACKGROUND: Hormone profile evaluation traditionally requires an expert review of results for adequate laboratory section test release. Analysis of these results using Boolean rules is an interesting alternative to reduce the number of results that require manual review. MATERIAL AND METHOD: We evaluated the utilization of Boolean rules using Instrument Manager software and Architect analyzer, mainly performing sex and thyroid hormones measurement. The intervention was evaluated on: a) number of rules and its easiness of construction; b) blind comparison of results evaluation by clinical pathologist (printed results) and set of rules in 940 consecutive tests. RESULTS: Rule creation was a complex and arduous task, especially due to hormonal profiles with several different request patterns. It was necessary to use a set of 153 Boolean (if...then) rules, in a specific order. This set of rules agreed with expert opinion in 97.9 percent (920 tests). Rules hold 25 tests (2.7 percent) and the clinical pathologist only nine tests. There was discordance in 20 cases; rules did not hold only two cases: a beta-hCG in a male patient (that prompted the creation of a new rule) and a complete thyroid profile lacking only TSH request (pathologist opted to review the original request). CONCLUSION: Creation of an efficient set of Boolean rules proved to be a complex task requiring both technical and logics knowledge, but allowing optimization of laboratory workload. We achieved excellent concordance between the set of rules and clinical pathologist manual review, in a safe, fast and low cost system.