Hashimoto’s Encephalopathy: An Unusual Cause of Autoimmune Encephalopathy in a Clinically and Biochemically Euthyroid Patient

Objectives: To highlight the occurrence of Hashimoto’s encephalopathy – a steroid-responsive encephalopathy associated with elevated antithyroid antibodies. Material and methods: We describe a clinically and biochemically euthyroid patient with an encephalopathy presenting with headache, mild confusion and personality changes for 6 weeks and tonic–clonic seizures upon admission Results: There was no obvious infective or metabolic cause. The patient had a high titre of antithyroid antibodies and responded to steroid therapy. Conclusion: This uncommon disease needs to be considered in patients presenting with neurological symptoms that remain unexplained after routine standard investigations, even when the patient is euthyroid. Early diagnosis is important, as this is a treatable condition.

Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant

Mutation of the BRAF gene is common in thyroid cancer. Follicular variant of papillary thyroid carcinoma is a variant of papillary thyroid carcinoma that has created continuous diagnostic controversies among pathologists. The aims of this study are to (1) investigate whether follicular variant of papillary thyroid carcinoma has a different pattern of BRAF mutation than conventional papillary thyroid carcinoma in a large cohort of patients with typical features of follicular variant of papillary thyroid carcinoma and (2) to study the relationship of clinicopathological features of papillary thyroid carcinomas with BRAF mutation. Tissue blocks from 76 patients with diagnostic features of papillary thyroid carcinomas (40 with conventional type and 36 with follicular variant) were included in the study. From these, DNA was extracted and BRAF V600E mutations were detected by polymerase chain reaction followed by restriction enzyme digestion and sequencing of exon 15. Analysis of the data indicated that BRAF V600E mutation is significantly more common in conventional papillary thyroid carcinoma (58% versus 31%, P = .022). Furthermore, the mutation was often noted in female patients (P = .017), in high-stage cancers (P = .034), and in tumors with mild lymphocytic thyroiditis (P = .006). We concluded that follicular variant of papillary thyroid carcinoma differs from conventional papillary thyroid carcinoma in the rate of BRAF mutation. The results of this study add further information indicating that mutations in BRAF play a role in thyroid cancer development and progression.

Promise and pitfalls of the Immunochip

Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Immunochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for immunogenetics gene mapping.

Genetics of ankylosing spondylitis and rheumatoid arthritis: Where are we at currently, and how do they compare?

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFκB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.

Alterações do Funcionamento da Glândula da Tiróide

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Relación entre la presencia de tiroiditis linfocítica con la gravedad y recurrencia/persistencia del carcinoma diferenciado de tiroides.

Introducción: Para el sistema endocrino la neoplasia más frecuente es el cáncer diferenciado de tiroides, con un claro incremento en su incidencia. Es importante encontrar asociaciones que posteriormente permitan establecer factores de riesgo y/o protectores claves en la estrategia terapéutica futura. Por lo que se investigó la relación entre la presencia de tiroiditis linfocítica con la gravedad y persistencia/recurrencia del carcinoma diferenciado de tiroides Materiales y métodos: se hizo un estudio de casos y controles de pacientes con carcinoma diferenciado de tiroides llevados a cirugía entre enero de 1997 y diciembre de 2012 en la Fundación Cardioinfantil, Bogotá, Colombia. Se evaluó la asociación entre la presencia de factores histopatológicos y la presencia de persistencia/recurrencia usando pruebas chi cuadrado y el OR. Para evaluar la presencia de asociación a nivel multivariado se utilizaron modelos de regresión binaria con enlace log log complementario. Resultados: la tiroiditis linfocítica no se asocia con la presencia de ninguna variable de severidad histopatológica. Sin embargo, la tiroiditis linfocítica se asoció con persistencia/recurrencia en presencia invasión vascular (OR 6.6 IC95% 1.4-32), invasión linfática (OR 5.4 IC95% 1.3-22.1), invasión de tejido peritiroideo (OR 1.0-12.3), vaciamiento central positivo (OR 5.1 IC 95% 1.0-2.6) y el, vaciamiento lateral positivo (OR 11.5 IC95% 1.0-12). Con un OR inclusive mayor respecto del grupo sin tiroiditis linfocítica en presencia de invasión linfática (OR 5.4 IC95% 1.3-22 vs 2.6 IC95% 1.2-5.6) y compromiso ganglionar en el vaciamiento lateral (OR 58 IC95% 7.1-476) independiente de la edad y el sexo. Conclusión: la tiroiditis linfocítica no se relaciona con marcadores de severidad histopatológica pero sí con mayor persistencia/recurrencia de la enfermedad.

How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs), these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1D), Sjögren's syndrome, and autoimmune thyroiditis (AITD). Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D), while for others it does not have a significant influence on the course of disease (i.e., SS) or no unanimous consensus exists (i.e., RA and MS).

Spondyloarthropathies in autoimmune diseases and vice versa

Polyautoimmunity is one of the major clinical characteristics of autoimmune diseases (ADs). The aim of this study was to investigate the prevalence of ADs in spondyloarthropathies (SpAs) and vice versa. This was a two-phase cross-sectional study. First, we examined the presence of ADs in a cohort of patients with SpAs (). Second, we searched for the presence of SpAs in a well-defined group of patients with ADs () including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). Among patients with SpAs, ankylosing spondylitis was observed in the majority of them (55.6%). There were two patients presenting with SS in the SpA group (1.4%) and 5 patients with autoimmune thyroiditis (3.5%). The global prevalence of ADs in SpAs was 4.86%. In the ADs group, there were 5 patients with SpAs (0.46%). Our results suggest a lack of association between SpAs and ADs. Accordingly, SpAs might correspond more to autoinflammatory diseases rather than to ADs.

Caracterizacion de nódulos tiroideos: concordancia entre estudio citopatologico y ecografia en la detección de nódulos malignos

: Los métodos imagenológicos para evaluar los nódulos tiroideos han sido motivo de estudio en las últimas décadas, especialmente la ecografía sobresale sobre las otras modalidades diagnósticas por su accesibilidad, portabilidad, y seguridad. A pesar de ello, las características ecográficas de cada nódulo han sido objeto de controversia en cuanto a su potencial detección de malignidad o benignidad. Se presenta un estudio de concordancia entre el estudio citopatológico y la ecografía para la caracterización nódulos tiroideos de naturaleza maligna y benigna, y su análisis de pruebas diagnósticas. Metodología: Se realizó un estudio descriptivo de concordancia con estudio de pruebas diagnósticas anidado. Se escogieron todos los pacientes con nódulos tiroideos a quienes se les realizó ecografía y estudio citopatológico de la lesión y se estudiaron los hallazgos ecográficos para evaluar su potencial diagnóstico para malignidad. Se incluyeron un total de 100 pacientes con nódulos tiroideos potencialmente malignos. La concordancia entre la ecografía en modo B y el estudio citopatológico fue moderada (índice kappa 0.55). La característica con mayor potencial para detectar malignidad fue la presencia de Microcalcificaciones (sensibilidad 75%, especificidad 92%).

Immunogenetics of drug-induced skin blistering disorders. Part II: Synthesis

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon examining the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events including Stevens-Johnson syndrome and Toxic epidermal necrolysis). New results from an exemplar study on shared precipitating and perpetuating inner causes with other related disease phenotypes including aphtous stomatitis, Behcets, erythema multiforme, Hashimoto's thyroiditis, pemphigus, periodic fevers, Sweet's syndrome and drug-induced multisystem hypersensitivity are presented. A call for a collaborative, wider demographic profiling and deeper immunotyping in suggested future work is made.

Autoimmune thyroid disease as a risk factor for angioedema in patients with chronic idiopathic urticaria: a case-control study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Avaliação audiológica em pacientes portadores de hipotireoidismo

Surdez no hipotireoidismo já foi descrita por diversos autores, porém a fisiopatologia é incerta. OBJETIVOS: Realizar avaliações audiológicas de pacientes com hipotireoidismo adquirido. MATERIAL E MÉTODOS: Grupos de estudo: hipotireoidismo (GH, n-30) e controle (GC, n-30). Parâmetros estudados: gênero, tempo do hipotireoidismo, co-morbidades, sintomas cócleo-vestibulares, exames bioquímicos e hormonais, limiares audiométricos, PEATE e EOAT. RESULTADOS: Todos os participantes eram mulheres; em GH 70% dos pacientes apresentavam tireoidite de Hashimoto e 60% tinham diagnóstico de hipotireoidismo há mais de 5 anos. Depressão e hipertensão foram as principais co-morbidades do grupo GH. Todos os pacientes de GH tinham valores elevados de TSH e 50% deles apresentavam diminuição de T4 livre. Surdez neurossensorial foi detectada em 22 orelhas de GH e em 7 de GC. PEATE mostrou-se normal nos participantes do GC e alterado em 10 orelhas do GH, havendo predomínio do aumento de L-V. EOAT estiveram ausentes em 12 orelhas de GH e em 4 de GC. CONCLUSÕES: Os pacientes com hipotireoidismo apresentaram mais sintomas cócleo-vestibulares, limiares audiométricos mais elevados, prolongamento das latências absolutas de L-V no PEATE e ausência ou redução as amplitudes das emissões otoacústicas. Tais alterações não estavam associadas aos níveis de TSH e T4 livre.

Hipotireoidismo em cães: aspectos gerais

Hypothyroidism is a common endocrine disorder in dogs caused by insufficient production and secretion of thyroid hormones. Most affected dogs have primary hypothyroidism that results from lymphocytic thyroiditis, idiopathic thyroid atrophy, or more rarely, neoplastic destruction. Secondary hypothyroidism resulting from inadequate secretion of thyrotropin (thyroid-stimulating hormone –TSH) from the pituitary gland is less commonly recognized. Tertiary hypothyroidism resulting from a deficiency of hypothalamic thyrotropin-releasing hormone (TRH) has not been documented in dogs. The diagnosis of hypothyroidism in dogs is made on the basis of clinical findings, results of routine laboratory and thyroid gland function tests and response to thyroid hormone replacement. Unfortunately, these tests have high sensitivity, but low specificity, for use in the diagnosis of hypothyroidism. Thyroid hormone supplementation is indicated for the treatment of confirmed hypothyroidism and for the diagnoses of the disease through clinical response to trial therapy