RESUMO
Resumen El objetivo de esta comunicación es proponer una guía de las formas decálculo de los intervalos de referencia (IR) en la población pediátrica ordenándolassegún su fortaleza metodológica. En primer lugar, el proceso recomendadopara definir un IR es el enfoque "directo", en el que se evalúanmuestras de sujetos considerados sanos. En segundo lugar, la convocatoria"indirecta", en la que a los resultados de las muestras de una base dedatos, se aplican criterios de exclusión y procesamientos estadísticos (métodosde Hoffmann y de Bhattacharya). Estos IR presentan poca diferenciacon los obtenidos por datos directos y se pueden considerar equivalentes,con la ventaja de su facilidad y sus costos más bajos. En tercer lugar, estánlos IR obtenidos de la bibliografía. La validación de los datos informadospor el fabricante es la última opción a tener en cuenta. Se reafirma laimportancia de contar con IR adecuados por sus aspectos clínicos y por laseguridad de los pacientes.
Abstract The aim of this communication is to propose a guide on the ways of calculating reference intervals (RI) in the pediatric population, ordering them according to their methodological strength. First, the recommended process to define an RI is the "direct" approach, in which samples of subjects considered healthy are evaluated. Secondly, the "indirect" approach, in which exclusion criteria and statistical processing are applied to the results ofthe samples in a database (Hoffmann and Bhattacharya methods). These RIs show little differences with those obtained by direct data and they can be considered equivalent, with the advantage of their ease and with lower costs. Thirdly, there are RIs that can be obtained from the bibliography. The validation of the data reported by the manufacturer is the last option to consider. The importance of having adequate RIs for their clinical aspects and for the safety of patients is reaffirmed.
Resumo O objetivo desta comunicação é propor um guia sobre as formas de cálculo dos intervalos de referência (IR) na população pediátrica, ordenando os mesmos de acordo com sua fortaleza metodológica. Emprimeiro lugar, o processo recomendado para definir um IR é a abordagem "direta", na qual sãoavaliadas amostras de indivíduos considerados saudáveis. Em segundo lugar, a abordagem "indireta",na qual critérios de exclusão e processamento estatístico (métodos de Hoffmann e Bhattacharya)são aplicados aos resultados das amostras em um banco de dados. Esses IR apresentam poucadiferença com os obtidos por dados diretos, podendo ser considerados equivalentes, com a vantagem de apresentarem facilidade e menor custo. Em terceiro lugar, os IR obtidos da bibliografia. A validadedos dados informados pelo fabricante é a última opção a ser considerada. A importância de termos IRadequados pelos seus aspectos clínicos e pela segurança dos pacientes é reafirmada.
Assuntos
Pediatria , Valores de Referência , Estatística , Segurança , Sistema Único de Saúde , Atrofias Musculares Espinais da Infância , Bases de Dados Bibliográficas , Comunicação , Custos e Análise de Custo , Estudo de Validação , Menores de Idade , MétodosRESUMO
CONTEXT: The low-dose (1 µg) ACTH test (LDT) is widely used to assess central adrenal insufficiency (CAI); however, the serum cortisol cutoff value is controversial. Salivary cortisol (SC) may be a more accurate measurement for CAI. OBJECTIVE: To assess a new maximum cutoff value of serum cortisol after LDT in pediatric patients, taking into account serum and SC measurements. DESIGN AND SETTING: Prospective study in a pediatric tertiary referral center. WORKING HYPOTHESIS: The combined analysis of serum and SC response to LDT might improve LDT for CAI diagnosis. PARTICIPANT AND OUTCOME MEASUREMENT: A total of 145 pediatric patients underwent LDT. Serum and SC levels were measured. A central adrenal sufficient (CAS) response was established according to the reference serum cortisol cutoff value of ≥497 nmol/L. RESULTS: The LDT study showed central adrenal sufficiency in 72 patients and CAI in 73 patients. Considering the lower quartile of maximum SC value (21 nmol/L) in the CAS group, an intermediate CAI (InCAI) group and a real CAI (RCAI) group were defined. Regarding the median maximum value of serum cortisol levels in the InCAI group, a new serum cortisol cutoff value of 450 nmol/L was established. Furthermore, 91% of the patients in the RCAI group were below this cutoff value. CONCLUSION: The combined evaluation of maximum serum and SC levels to LDT might be useful to define an InCAI group and to avoid unnecessary hormone replacement therapy. However, rigorous patient follow-up is required.
Assuntos
Insuficiência Adrenal/diagnóstico , Hormônio Adrenocorticotrópico/farmacologia , Hidrocortisona/sangue , Sistema Hipófise-Suprarrenal/fisiopatologia , Glândulas Salivares/metabolismo , Adolescente , Insuficiência Adrenal/sangue , Hormônio Adrenocorticotrópico/sangue , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pediatria , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estudos Prospectivos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Las actividades del laboratorio de análisis clínicos están fuertemente identificadas con el ritmo del cambio tecnológico. En los últimos treinta años se vive un cambio de época que afecta la cultura y la experiencia humana en todos sus aspectos. Este cambio modifico el modelo de producción. En el laboratorio ha incorporado tecnología que combina la química, la robótica, la óptica y la informática, y se ha impuesto como premisa externa de cambio un modelo de gestión global que afecta la forma de trabajo, la gestión y el rol de los profesionales (bioquímicos y técnicos). El hospital Garrahan inscribe su historia dentro de este periodo histórico y el proceso de cambio ha generado y genera incertidumbre, resistencia y adecuaciones al nuevo paradigma impuesto. Nos fijamos como objetivo analizar el impacto de este cambio sobre la gestión de procesos del laboratorio de nuestro hospital. Comprobamos que la demanda del laboratorio se incrementó al ritmo del crecimiento de consultas y egresos de pacientes, y de como este aumento demando adecuaciones de gestión, modificaciones arquitectónicas, incorporación de tecnologías (algunas emergentes), aumento en la trazabilidad de muestras y resultados, y mejoras en la seguridad del paciente en todos sus aspectos. Describimos el nuevo paradigma, sus ventajas, las adecuaciones hechas y los tiempos en que se fueron realizados. Concluimos sugiriendo un rol para los profesionales del laboratorio en función del paradigma en curso
Activities at the laboratory of clinical analysis are closely related to the pace of technological change. Over the past 30 years there has been a change of times affecting human culture and experience in all its aspects. This change has modified the model of production. The laboratory has incorporated technology combining chemistry, robotics, and optics, as well as information technology, and the premise of a global management model has been imposed affecting the way of working, administration, and the role of professionals (biochemists and technicians). Garrahan hospital has written its own history in this historical period and process of change has produced uncertainty, resistance as well as adaptation to this new paradigm. Our aim has been to analyze the impact of this change on the management of processes of the laboratory of our hospital. We have observed that the demand of the laboratory has increased at the same pace as the increase of patient visits and discharges. This increase has required modifications in the management and facilities, incorporation of new technologies (some of them state of the art), improved traceability of the samples and results, and improvements in patient safety in all aspects. Here we describe the new paradigm, its advantages, adaptations made, and improved times introduced. In our conclusions, we consider the new role for laboratory professionals in this paradigm.
Assuntos
Serviços de Laboratório Clínico/organização & administração , Serviços de Laboratório Clínico/estatística & dados numéricos , Técnicas de Laboratório Clínico/instrumentação , Equipamentos de Laboratório , Desenvolvimento Tecnológico , Automação , Segurança do Paciente , Gestão da Qualidade TotalRESUMO
BACKGROUND: Central adrenal insufficiency (CAI) is due to a decrease of CRH and/or ACTH secretion. ACTH-dependent dehydroepiandrosterone sulphate (DHEAS) has been postulated as a possible marker of adrenal function in adult patients. AIMS: To evaluate the usefulness of basal serum DHEAS determination to diagnose CAI in pubertal patients with a suspected diagnosis of CAI. METHODS: Ninety-four pubertal patients suspected of having CAI were divided into two groups according to sufficient (group 1) or insufficient (group 2) low-dose ACTH test serum cortisol response. Concordance with low (<2.5th percentile) or normal (≥2.5th percentile) basal serum DHEAS levels for age and sex, respectively, was analysed. RESULTS: Fifty patients (53.2%) in group 1 and 44 (46.8%) in group 2 were included. The median value of serum DHEAS levels in group 2 (0.7 µmol/l, interquartile range 0.44-1.49) was significantly lower than in group 1 (2.13 µmol/l, interquartile range 0.87-3.5; p < 0.03). Nevertheless, serum basal DHEAS levels as a diagnostic marker of CAI showed 39% sensitivity and 80% specificity. CONCLUSION: In pubertal patients, basal serum DHEAS levels do not seem to be a useful tool to diagnose either sufficiency or insufficiency of secondary adrenal function.
Assuntos
Insuficiência Adrenal/sangue , Desidroepiandrosterona/sangue , Puberdade/sangue , Adolescente , Hormônio Adrenocorticotrópico/sangue , Adulto , Biomarcadores/sangue , Criança , Humanos , Hidrocortisona/sangue , MasculinoRESUMO
CONTEXT: Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia. OBJECTIVE: The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency. PATIENT: Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism. RESULTS: We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization. CONCLUSIONS: A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Mitocôndrias/metabolismo , Mutação de Sentido Incorreto , Fosfoproteínas/genética , Sinais Direcionadores de Proteínas/genética , Animais , Células COS , Criança , Chlorocebus aethiops , Transtornos do Desenvolvimento Sexual/genética , Feminino , Genes Dominantes/genética , Humanos , Recém-Nascido , Masculino , Mutação de Sentido Incorreto/fisiologia , Linhagem , Polimorfismo de Nucleotídeo Único/fisiologia , Estrutura Terciária de Proteína/genética , Transporte Proteico/genéticaRESUMO
Changes in the clinical presentation of diabetes mellitus in childhood and adolescence associated with obesity have resulted in an overlap of the two most common types of diabetes with a greater clinical heterogeneity. In order to characterize the type of diabetes at onset and assess the effect of obesity, 50 children with diabetes were studied. The patients were divided into two groups according to their nutritional status at diagnosis (over-weight/obese vs. normal weight). Insulin reserve was evaluated by measuring basal C-peptide and stimulated C-peptide in response to a mixed meal (MMTT) as well as HLA-DQB1 genotype, antibodies, and family history of risk factors for metabolic disease. Of all 50 patients, 38% was overweight/obese, 84% had a positive family history of metabolic syndrome, 82% had positive antibodies, and 100% were positive for the high-risk HLA-DQB1 genotype. No significant differences were found in fasting C-peptide or glycemic index/C-peptide levels between the two groups. In the overweight/obese group C-peptide response to MMTT showed higher levels at 60 and 120 minutes (p = 0.02 and 0.03) and the area under the curve for C-peptide was also higher (1.77 ng / ml vs. 5.5 ng/ ml, p = 0.0007) than in the normal-weight group. In conclusion, overweight/obese patients with type 1A diabetes had a greater pancreatic reserve, suggesting that nutritional status may accelerate disease onset.
Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Adolescente , Autoimunidade , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Criança , Diabetes Mellitus Tipo 1/genética , Feminino , Genótipo , Glutamato Descarboxilase/sangue , Cadeias beta de HLA-DQ/sangue , Humanos , Anticorpos Anti-Insulina/sangue , Masculino , Síndrome Metabólica/complicações , Obesidade/complicações , Estudos Prospectivos , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/sangue , Fatores de RiscoRESUMO
In humans, steroidogenic factor 1 (NR5A1/SF-1) mutations have been reported to cause gonadal dysgenesis, with or without adrenal failure, in both 46,XY and 46,XX individuals. We have previously reported extreme within-family variability in affected 46,XY patients. Even though low ovarian reserve with preserved fertility has been reported in females harboring NR5A1 gene mutations, fertility has only been observed in one reported case in affected 46,XY individuals. A kindred with multiple affected members presenting gonadal dysgenesis was studied. Four 46,XY individuals presented severe hypospadias at birth, one of them associated with micropenis and cryptorchidism. The other 3 developed spontaneous male puberty, and 1 has fathered 5 children. Four 46,XX patients presented premature ovarian failure (one of them was not available for the study) or high follicle-stimulating hormone levels. Mutational analysis of the NR5A1 gene revealed a novel heterozygous mutation, c.938GâA, predicted to cause a p.Arg313Hys amino acid change. A highly conserved amino acid of the ligand-binding domain of the mature protein is affected, predicting abnormal protein function. We confirm that preserved fertility can be observed in patients with a 46,XY disorder of sex development due to heterozygous mutations in the NR5A1 gene.