Enfermedades autoinmunitarias asociadas a diabetes mellitus tipo 1A / Autoimmune diseases in type 1A diabetes mellitus

Type 1A diabetes (DM1A) is an autoimmune disease that comprises 10% of patients with diabetes mellitus. Its frequency is gradually increasing in countries like Mexico. Patients with DM1A commonly have hypothyroidism, Addison disease, celiac disease and less common diseases such as polyglandular syndrome. These diseases are related to susceptibility genes such as HLA, CTLA-4 and PTPN22, which induce central and peripheral immunologic tolerance. This review article emphasizes the importance of searching other autoimmune diseases in patients with DM1A, to improve their prognosis and quality of life.

Rastreio de síndrome poliglandular autoimune em uma população de pacientes com diabetes melito tipo 1 / Screening for autoimmune polyglandular syndrome in a cohort of patients with type 1 diabetes mellitus

OBJETIVO: Caracterizar uma população de pacientes com diabetes melito tipo 1 (DMT1) relativamente à presença de outras entidades autoimunes que permitam estabelecer o diagnóstico de síndrome poliglandular autoimune (SPGA). SUJEITOS E MÉTODOS: Incluímos 151 pacientes com DMT1. Analisamos os seguintes parâmetros clínicos: gênero, idade atual, duração da doença, antecedentes pessoais de patologia autoimune e antecedentes familiares de diabetes melito. Submetemos cada doente a um estudo laboratorial com o objetivo de detectar a presença de marcadores imunológicos para a tireoidite, insuficiência adrenocortical, gastrite e doença celíaca, e eventual disfunção associada. RESULTADOS: Coorte com 51,7% homens, idade média atual de 33,4 ± 13 anos e duração da doença de 14,4 ± 9,6 anos. Antecedentes pessoais de autoimunidade presentes em 2% da amostra e história familiar de diabetes melito em 31,1%. A frequência de marcadores imunológicos foi de 24% para a tireoidite, 9,4% para a insuficiência adrenocortical, 17,2% para a gastrite e 2% para a doença celíaca. Foi diagnosticada SPGA em 25,2% dos pacientes. O risco de SPGA e tireoidite autoimune foi superior em mulheres. A duração da doença correlacionou-se diretamente com a presença de autoanticorpos gástricos e inversamente com a positividade dos anticorpos anti-ilhota, antiglutamato descarboxilase e antitirosina fosfatase. Constatou-se a existência de uma associação entre os marcadores imunológicos da tireoidite e gastrite, bem como entre a doença celíaca e insuficiência adrenocortical. CONCLUSÃO: Atendendo à frequência e ao prognóstico inerente à SPGA, a necessidade de realizar rastreio em pacientes com DMT1 é enfatizada. O diagnóstico atempado de outras doenças autoimunes permitirá individualizar o tratamento e seguimento do doente.

OBJECTIVE: To characterize a cohort of patients with type 1 diabetes mellitus (T1DM) on the presence of other autoimmune disorders that could establish the diagnosis of autoimmune polyglandular syndrome (APS). SUBJECTS AND METHODS: We included 151 patients with T1DM. The following clinical parameters were analyzed: gender, current age, disease duration, previous history of autoimmune disorders, and familial history for diabetes mellitus. Each patient was analyzed to detect autoimmune markers of thyroiditis, adrenocortical insufficiency, gastritis, and celiac disease, as well as possible associated dysfunctions. RESULTS: A cohort with 51.7% males, average current age of 33.4 ± 13 years and disease duration of 14.4 ± 9.6 years was analyzed. Previous history of autoimmunity was found in 2%, and familial history for diabetes mellitus in 31.1% of the cohort. Frequency of autoimmune markers was 24% for thyroiditis, 9.4% for adrenocortical insufficiency, 17.2% for gastritis, and 2% for celiac disease. APS was diagnosed on 25.2% of the patients. APS and autoimmune thyroiditis risk was higher in females. Disease duration correlated directly with gastric autoantibodies, and inversely with positive islet cell, glutamic acid decarboxylase, and tyrosine phosphatase antibodies. We noticed a correlation between autoimmune markers for thyroiditis and gastritis, as well as between celiac disease and adrenocortical insufficiency. CONCLUSION: Considering APS prevalence and prognosis, the need for APS screening in patients with T1DM is emphasized. Early diagnosis of other autoimmune disorders will enable us to adjust each patient treatment and follow-up.

Autoimmune polyendocrine syndrome type 1: case report and review of literature / Síndrome poliglandular autoimune tipo 1: descrição de caso e revisão da literatura

Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome.

Síndrome poliglandular autoimune tipo 1 é uma rara desordem autossômica recessiva caracterizada por ataque autoimune a diversos órgãos. A doença é causada por mutações no gene AIRE (autoimmune regulator), resultando em uma proteína AIRE defeituosa, proteína esta essencial para a manutenção da autotolerância. As manifestações clínicas são extremamente variáveis. A tríade clássica é composta por candidíase mucocutânea crônica, hipoparatiroidismo e insuficiência adrenal, porém diversos outros componentes podem estar presentes. A base do tratamento é a reposição das diversas deficiências, e os pacientes devem ser acompanhados por toda a vida. Este artigo descreve o caso de uma paciente com a síndrome e apresenta uma revisão sobre a epidemiologia, quadro clínico, aspectos imunogenéticos, diagnóstico e tratamento da desordem, de acordo com a literatura publicada.

Síndrome Poliglandular Autoinmune Tipo II: Posible Asociación con HLA DRB1*-DQB1* / Possible association of Type II Autoimmune Polyendrocrine Syndrome with HLA DRB1*-DQB1*

Los síndromes poliendocrinos autoinmunes (APS) asocian enfermedades endocrinas autoinmunes con otros desórdenes autoinmunes no endocrinos. El APS tipo II se caracteriza por compromiso primario suprarrenal, tiroideo y/o DM tipo I. Presentamos un paciente masculino de 46 años que fue internado por astenia, adinamia, hiporexia, severa disminución de peso, mareos y vómitos. Antecedente de obesidad y diabetes diagnosticada 3 años antes. Presentaba hipotensión arterial, hiperpigmentación de mucosas y pliegues, anemia, hiponatremia e hipoglucemias frecuentes a pesar de la disminución de la dosis de insulina. Se diagnosticó insuficiencia suprarrenal, concomitantemente con hipotiroidismo y diabetes tipo 1, todas de origen autoinmune, iniciándose reemplazo hormonal. Se encontró una posible asociación del HLA DRB1*-DQB1* en los estudios genéticos. Conclusiones: Nuestro paciente presenta el HLA DQB1*0302 descripto en el APSII, pero el HLA DRB1 *08 encontrado no está descripto en este síndrome ni en ningún otro desorden autoinmune. En pacientes con Diabetes tipo 1 que disminuyan el requerimiento insulínico, habría que descartar insuficiencia suprarrenal, un componente del APS II, como factor etiológico, a pesar de su baja prevalencia.

Autoimmune polyendocrine syndromes (APS) are the association of autoimmune endocrine diseases with other non-endocrine autoimmune disorders. Type II APS is defined by occurrence of Addison´s disease with thyroid autoimmune disease and/or type 1 diabetes mellitus. We present a 46-year-old male patient who was hospitalized because of asthenia, adynamia, hyporexia, severe loss of weight, dizziness and vomiting. Diabetes mellitus had been diagnosed 3 years earlier when he was obese. He presented arterial hypotension, anemia, darkening of the skin and oral mucosa, hyponatremia and frequent hypoglycemia although his insulin dose was decreased. Adrenal insufficiency was diagnosed together with hypothyroidism and type 1 diabetes, all of them of autoimmune origin. Hormonal replacement treatment was initiated. Genetic studies were performed and a new polymorphism was found. Conclusions: HLA DRB1 *08 found in our patient has not been described in APS II or in any other autoimmune disorders. He also has HLA DQB1*0302 described in previous reports related to APS II. In type 1 diabetic patients whose insulin requirement decreases, it would be advisable to rule out adrenal insufficiency, a component of APS II, as an etiologic factor in spite of its low prevalence. In diabetic obese patients (mainly young) who lose weight without a defined cause, type 1 diabetes mellitus should be excluded.

Autoimmune polyglandular syndrome type 1 in Saudi children

To describe the clinical, biochemical, and immunological manifestations of autoimmune polyglandular syndrome type 1 [APS-1] in a Saudi population. The medical files of 7 consanguineous Saudi families with 20 affected siblings were retrospectively reviewed. They were followed at the Pediatric Endocrinology Clinic, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia for a mean duration of 6 years [January 2000 to December 2009]. The age of the affected children ranged from 2-17 years. The included patients had at least 2 out of the 3 major clinical diagnostic criteria of APS-1. Fourteen children had neonatal chronic mucocutaneous candidiasis affecting the nails and mouth. The most commonly presenting endocrine disease among APS-1 patients was hypoparathyroidism. Eight patients had autoimmune Addison's disease. Hypothyroidism was diagnosed in 3 patients, and 9 patients had alopecia universalis. Other endocrine and autoimmune disorders were infrequently seen including type 1 diabetes, growth hormone deficiency, celiac disease, autoimmune hepatitis, and keratoconjuctivitis. Autoimmune polyglandular syndrome type 1, although an uncommon disorder in Saudi children affects multiple endocrine glands, and is associated with several autoimmune diseases where alopecia universalis is a common finding

Diabetes melito tipo 1 no contexto das poliendocrinopatias auto-imunes: [revisão] / Type 1 diabetes and autoimmune polyendocrine syndromes: [review]

Três entidades clínicas distintas, causadas por desarranjos genéticos, estão associadas a múltiplas desordens auto-imunes: síndrome linfoproliferativa auto-imune, poliendocrinopatias auto-imunes (APSs) e desregulação imune, poliendocrinopatia, enteropatia ligada ao X (IPEX). O diabetes melito auto-imune ou tipo 1 (DM1) pode estar presente nas APSs e na IPEX. A APS-1 caracteriza-se pela associação de candidíase crônica, hipoparatireoidismo e insuficiência adrenal auto-imune ou idiopática (doença de Addison), no entanto, o diabetes melito tipo 1 pode estar presente em até 12 por cento dos casos. A APS-2 inclui a doença de Addison (sempre presente), a doença tireoidiana auto-imune e o diabetes melito tipo 1, enquanto na APS-3 a doença tireoidiana se associa a outra doença imunológica, excluindo a insuficiência adrenal e o hipoparatireoidismo, e a APS-4 é composta por combinações diferentes das descritas anteriormente. Já a IPEX caracteriza-se por alteração rara da regulação auto-imune que resulta doenças auto-imunes de início precoce, envolvendo pâncreas, tireóide, intestino com diarréia secretora grave, eczema e anemia. O diagnóstico e o tratamento das doenças componentes das poliendocrinopatias e da IPEX são semelhantes ao da patologia na forma isolada.

Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.

Heterogeneidade do diabetes melito tipo 1 / Heterogeneity of type 1 diabetes mellitus

O diabetes melito tipo 1 (DM1) caracteriza-se pela deficiência de insulina por causa da destruição das células-beta pancreáticas. O DM1 atualmente é classificado em dois subtipos: um auto-imune (DM1A) e outro não auto-imune (DM1B). O DM1A poligênico (isolado ou associado a outras doenças auto-imunes) é a forma mais prevalente. O DM1A pode fazer parte de síndromes raras em virtude de alterações monogênicas [gene regulador da auto-imunidade (AIRE)] e mutações no gene FOX-p3. O DM1B corresponde de 4 por cento a 7 por cento do DM1 e pode incluir formas não clássicas, como o diabetes fulminante e o DATC. Jovens com DM1A e sinais de resistência à insulina associados têm sido denominados de diabetes duplo (DD), tipo 1 e tipo 2. Nessa revisão são discutidas as patofisiologias e as características clínicas das formas raras de DM1A, o DM1B, as formas atípicas de DM1 não auto-imune e as inter-relações entre a inflamação subclínica da obesidade e o processo auto-imune do DM1A no DD. Em resumo, apresentamos o conceito de heterogeneidade do DM1.

Type 1 diabetes (T1D) comprises all forms of autoimmune-mediated and idiopathic beta-cell destruction leading to absolute insulin deficiency. The etiological heterogeneity of T1D has been recognized for the last decades, but it has been divided into only two subtypes so far: autoimmune (T1D)A and non-autoimmune (T1D)B mediated. Polygenic T1DA (isolated or associated to other autoimmune diseases) is the most prevalent type of T1D. T1DA might be part of rare monogenic syndromes related to mutations in the autoimmune regulator gene (AIRE) and FOXp3. Non-autoimmune forms of T1D correspond to approximately 4 to 7 percent of newly diagnosed T1D and include T1DB, as well as other types of atypical diabetes, for example fulminant type 1 diabetes and adult ketosis-prone diabetes. A new expression of diabetes in young with insulin resistance and obesity, along with the presence of pancreatic autoimmunity markers, namely auto-antibodies to islet cell antigens, is called double diabetes (DD), T1DA plus type 2 diabetes. Evidence has been collected concerning the potential effect of obesity-linked cytokines in amplifying the autoimmune response in DD. Therefore all these issues are presented and discussed in this review as the concept of heterogeneity of Type 1 Diabetes.

Anticuerpos anti 21 hidroxilasa séricos en pacientes con anticuerpos antifracción microsomal: síndrome poliendocrino autoinmune / Seric 21- hydroxilase antibodies in patients with anti-microsomal fraction antibodies: autoimmune polyendocrine syndrome

El síndrome poliendocrino autoinmune (SPA) es la asociación de enfermedades endocrinas autoinmunes con otros desórdenes autoinmunes no endocrinos. Los tipos 1, 2 y 4 presentan adrenalitis autoinmune, esto indica la presencia de autoanticuerpos, y su marcador serológico específico es el anti 21 hidroxilasa (a21-OH). El SPA tipo 2 es la asociación de adrenalitis, enfermedad tiroidea y/o diabetes mellitus inducidas por autoanticuerpos. Como componentes menores, pueden estar asociados entre otros, vitiligo, alopecia y miastenia. Nuestros objetivos fueron: establecer la prevalencia de a21-OH séricos en pacientes con anticuerpos anti fracción microsomal (AFM) positivos, enfermedad tiroidea autoinmune y/o afecciones endocrinas y no endocrinas autoinmunes; diagnosticar formas incompletas de SPA y estudiar individuos con probable riesgo de progresión a un SPA completo. Estudiamos 72 pacientes AFM positivos y 60 sujetos tomados como grupo control, AFM negativos. Hallamos a21-OH elevados en dos pacientes: A= 47 U/ml, hipotiroidismo autoinmune y miastenia; y B= 8.75 U/ml, hipotiroidismo autoinmune y vitiligo; ambos con ausencia de insuficiencia adrenal. La prevalencia de a21-OH encontrada fue del 2.8%. Las pacientes A y B corresponden a un SPA tipo 2 incompleto y latente en relación al componente adrenal. Considerando a los a21-OH marcadores de enfermedad autoinmune latente, el eventual riesgo de evolución hacia la afección clínica sugiere la necesidad de estrechos controles clínicos y bioquímicos periódicos.

Autoimmune polyendocrine syndrome (APS) is the association of autoimmune endocrine diseases, with other autoimmune nonendocrine disorders. APS types 1, 2 and 4 include autoimmune adrenalitis; this suggests the presence of autoantibodies. A specific serological marker for these is the anti 21- hydroxilase autoantibody (a21-OH). APS type 2 is the association of autoimmune adrenalitis, to autoimmune thyroid disease and/or diabetes mellitus, all these are induced by autoantibodies. Alopecia, vitiligo, myasthenia and other manifestations can be minor components. We sought to establish the prevalence of seric a21-OH in patients with positive anti-microsomal fraction autoantibodies, autoimmune thyroid disease and/or non-endocrine autoimmune diseases. We also aimed to diagnose incomplete forms of APS and to follow up patients at risk of progression to complete forms of APS. A population of 72 patients and another of 60 controls with negative anti-microsomal fraction autoantibodies were studied. Elevated seric a21-OH were found in two patients. Patient A with 47 U/ml had autoimmune hypothyroidism and myasthenia; and patient B with 8.75 U/ml had autoimmune hypothyrodism and vitiligo; they both lacked adrenal insufficiency. Seric a21-OH had a prevalence of 2.8%. Regarding the adrenal component, patients A and B had an incomplete and latent APS type 2. Considering a21-OH as markers of latent endocrine autoimmune diseases and taking into account the eventual risk of developing clinical manifestations, periodic biochemical and clinical follow-ups are recommended.