Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway in vivo and in vitro / 医学前沿

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.

Liver involvement in endocrine diseases / 中华肝脏病杂志

As a secondary endocrine organ, the liver is closely related to the endocrine system. Liver involvement is not uncommon in endocrine diseases, such as hyper/hypothyroidism, diabetes, dysfunction of adrenal and gonadal. It can be manifested in a variety of forms, including hepatocyte injury (elevated transaminase), bile duct injury (cholestasis), hepatocyte steatosis, vascular injury and liver tumor. Direct and indirect liver injury caused by abnormal hormone levels and side effects of drugs for the treatment of endocrine diseases are common pathogenesis. In addition, endocrine diseases can be concomitant with liver diseases, such as autoimmune thyroiditis and autoimmune hepatitis. Systemic diseases can also involve the endocrine system and liver at the same time, such as systemic lupus erythematosus and IgG4 related diseases. For patients with unexplained liver injury, endocrine system diseases should be considered as the differential diagnosis.

Diagnóstico de hepatitis autoinmune / Diagnosis of autoimmune hepatitis

La hepatitis autoinmune es una enfermedad inflamatoria del hígado de etiología desconocida, que se caracteriza por la presencia de autoanticuerpos y niveles altos de globulinas séricas. Afecta a ambos sexos, a todos los grupos de edad, y se ha descrito en todas las razas. Tiene una amplia variedad de presentación clínica, lo que la convierte en un reto diagnóstico para el médico. La forma de presentación más común es la hepatitis aguda; sin embargo, un porcentaje no despreciable de pacientes es asintomático y hasta el 40% de los casos tiene cirrosis al momento del diagnóstico. El diagnóstico se basa en: 1) la medición de autoanticuerpos, como los antinucleares (ANA), los antimúsculo liso (ASMA), y los antimicrosomales de hígado y riñón (anti-LKM-1); 2) la detección de niveles séricos elevados de globulinas (especialmente IgG); 3) descartar otras etiologías de hepatitis crónica; y, 4) los hallazgos histológicos, los cuales además de confirmar el diagnóstico, ayudan a establecer la severidad. Se han desarrollado escalas y puntajes diagnósticos que permiten una mejor aproximación a dicha patología sin reemplazar el juicio del médico, por lo que deben ser interpretados bajo un adecuado contexto clínico. Un diagnóstico apropiado puede permitir el inicio oportuno de tratamiento con el fin de disminuir la progresión y el desarrollo de complicaciones.

Autoimmune hepatitis is an inflammatory disease of the liver of unknown etiology. It is characterized by the presence of autoantibodies and elevated levels of serum globulins. It affects both genders, all age groups and has been described in all races. It has a wide variety of clinical manifestations, so it remains a diagnostic challenge for physicians. The most common form of manifestation is acute hepatitis, however a non-negligible percentage of patients is asymptomatic, and up to 40% of cases have cirrhosis at the time of diagnosis. The diagnosis is based on: 1) measurement of autoantibodies, such as antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), and liver/kidney microsomal type 1 antibodies (anti-LKM-1); 2) detection of elevated serum levels of globulins (especially IgG); 3) exclusion of other causes of chronic hepatitis; and, 4) histological findings, which also confirm the diagnosis and help determine its severity. Diagnostic scales and scores have been developed to allow a better approach to this pathology without replacing the clinical judgment, so they must be interpreted under an adequate clinical context. A proper diagnosis can allow a timely initiation of treatment in order to decrease the progression and the development of complications.

Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings, histological profile, treatments, and outcomes / Hepatite autoimune em 828 crianças e adolescentes brasileiros: achados clínicos e laboratoriais, perfil histológico, tratamentos e resultados

Abstract Objective: This large study with a long-term follow-up aimed to evaluate the clinical presentation, laboratory findings, histological profile, treatments, and outcomes of children and adolescents with autoimmune hepatitis. Methods: The medical records of 828 children and adolescents with autoimmune hepatitis were reviewed. A questionnaire was used to collect anonymous data on clinical presentation, biochemical and histological findings, and treatments. Results: Of all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmune hepatitis-2. The female sex was predominant in both groups. The median age at symptom onset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis 1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and 58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher for autoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-fold higher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were significantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels were lower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochemical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6% underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmune hepatitis-2: 2.4%). Conclusions: In this large clinical series of Brazilian children and adolescents, autoimmune hepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higher disease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.

Resumo Objetivo: Este estudo com acompanhamento de longo prazo visou a avaliar o quadro clínico, os achados laboratoriais, o perfil histológico, os tratamentos e os resultados de crianças e adolescentes com hepatite autoimune. Métodos: Foram analisados os prontuários médicos de 828 crianças e adolescentes com HAI. Foi usado um questionário para coletar os dados anônimos sobre o quadro clínico, os achados bioquímicos e histológicos e os tratamentos. Resultados: De todos os pacientes, 89,6% tinham hepatite autoimune-1 e 10,4% hepatite autoimune-2. O sexo feminino foi predominante nos dois grupos. A idade média no início dos sintomas foi 111,5 (6; 210) e 53,5 (8; 165) meses nos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente. Foi observado início clínico agudo em 56,1% e 58,8% e sintomas insidiosos em 43,9% e 41,2% dos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente. A probabilidade de insuficiência hepática foi 1,6 vezes maior para hepatite autoimune-2; 3,6% e 10,6% dos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente, apresentaram insuficiência hepática fulminante; o risco foi 3,1 vezes maior para hepatite autoimune-2. Os níveis de gamaglobulina e imunoglobulina G foram significativamente maiores nos pacientes com hepatite autoimune-1, ao passo que os níveis de imunoglobulina A e C3 foram menores em pacientes com hepatite autoimune-2; 22,4% dos pacientes apresentaram cirrose e a remissão bioquímica foi atingida em 76,2%. A taxa de sobrevida atuarial foi de 93,0%. Um total de 4,6% pacientes foram submetidos a transplante de fígado e 6,9% morreram (hepatite autoimune-1: 7,5%; hepatite autoimune-2: 2,4%). Conclusões: Nesta grande série clínica de crianças e adolescentes brasileiros, a hepatite autoimune-1 foi mais frequente e os pacientes com hepatite autoimune-2 mostraram maiores taxas de remissão da doença com respostas mais rápidas aos tratamentos. Os pacientes com hepatite autoimune-1 apresentaram maior risco de óbito.

¿Pensar en hepatitis autoinmune precozmente evita la cirrosis? / Does early autoimmune hepatitis diagnose prevent from cirrhosis?

La hepatitis autoinmune (HAI) es una hepatopatía inflamatoria crónica y progresiva, que afecta predominantemente al sexo femenino y se caracteriza por la presencia de autoanticuerpos, elevación de aminotransferasas e hipergammaglobulinemia. Evoluciona rápidamente a cirrosis en pacientes no tratados, por lo que su diagnóstico precoz es indispensable. El propósito de este estudio es evaluar el tiempo promedio entre el inicio de los síntomas y el diagnóstico, así como su correlación con la presencia de cirrosis. Se realizó un estudio analítico, retrospectivo, no experimental. Se revisaron las historias clínicas de 51 pacientes que acudieron a la consulta de gastroenterología del hospital de niños J.M. de los Ríos desde abril de 1996 hasta septiembre de 2010 diagnosticados de HAI según criterios clínicos, serológicos e histológicos. Se excluyeron 3 pacientes por presentar patologías asociadas o estar recibiendo tratamiento inmunosupresor previo. La edad varió entre 2 y 15 años (media 8,3±3,2 DE); prevaleciendo el sexo femenino (72,9%). La clínica predominante fue ictericia (81,3%), coluria (47,9%) y dolor abdominal (39,5%). El diagnóstico se realizó en promedio 8,4 ± 7,3 meses luego del inicio de los síntomas. 50% se diagnosticó en los primeros 6 meses, de éstos 54,2% presentó cirrosis y 33,3% fibrosis. La HAI debe considerarse en pacientes pediátricos con clínica de hepatopatía inflamatoria a fin de realizar un diagnóstico oportuno y precoz debido a su rápida evolución a cirrosis

Autoimmune hepatitis (HAI) is a progressive chronic inflammatory hepatopathy with higher prevalence in females characterized by autoantibodies presence, elevation of aminotransferases and hipergammaglobulinemia. Another important characteristic is that it can develop into a rapid cirrhosis, so early diagnosis is vital. The purpose of our study is to evaluate the time spent between initial symptoms and final diagnosis, and it relation with the presence of cirrhosis. An analytic, retrospective non experimental study was performed. We reviewed the clinical records of 51 patients from April 1996 to September 2010 who attended the consultation of gastroenterology in the J. M. de los Ríos Children's Hospital with the diagnose of HAI according to clinical criteria, serological and histological. We excluded 3 patients for two reasons. 1. They were presenting associated pathologies 2. They were receiving immunosuppressive treatment. The ages vary from 2 to 15 years old (mean 8.3±3.2 ED); female prevail with (72.9%). The predominant symptoms were jaundice (81.3%), coluria (47.9%) and abdominal pain (39.5%). The diagnosis was made on average 8.4 ± 7.3 months after the beginning of the symptoms. 50% were diagnosed in the first 6 months, from these 54.2% presented with cirrhosis and 33,3% with fibrosis. HAI must be considered in pediatric patients with inflammatory hepatopathy clinical history in order to make an early and opportune diagnosis due to its rapid evolution to cirrhosis

Hepatitis autoinmune en niños: clínica y manejo / Autoimmune hepatitis in children: clinical and management

La hepatitis autoinmune (HAI), es una enfermedad inflamatoria crónica y progresiva, que se caracteriza histológicamente por un denso infiltrado de células mononucleares en vías portales, y cuya patogenia se le atribuye a una reacción inmune frente a autoantígenos hepatocelulares demostrado serológicamente por la presencia de autoanticuerpos específicos y aumento en los niveles de las aminotransferasas y de inmunoglobulina tipo IgG, en ausencia de una etiología conocida. Son reconocidos dos tipos de HAI en la infancia: HAI tipo I, que se caracteriza por la presencia de anticuerpos (anti músculo liso SMA) y/o antinucleares (ANA), y la HAI tipo II,que se caracteriza por anticuerpos antimicrosomales de riñón hígado (anti-LKM). La etiología de la HAI es desconocida, aunque tanto factores genéticos como ambientales están implicados en su expresión. El fenotipo clínico de la HAI en niños varía en gran medida, va desde una evolución leve a un curso fulminante. La HAI es sensible a la terapia inmunosupresora. El trasplante hepático está indicado en pacientes que presentan insuficiencia hepática fulminante (encefalopatía) y los que desarrollan enfermedad hepática terminal.

Autoimmune hepatitis (HAI) is a chronic and progressive inflammatory disease, characterizedhistologically by a dense infiltrate of mononuclear cells in the process portals, and whose pathogenesis is attributed to an immune response against hepatocellular autoantigens demonstratedserologically by the presence of specific autoant ibodies and increased levels of aminotransferases and immunoglobulin IgG, in the absence of known etiology. Recognized two types of HAI in childhood: type I, characterized by the presence of antibodies (smooth muscle anti SMA) and / or antinuclear (ANA) and type II, characterized by anti-microsomal antibodies liver kidney (anti-LKM). The etiology of HAI is unknown, a l though both gene t i c and environmental factors are involved in its expression. The clinical phenotype of the HAI in children varies greatly, ranging from a slight evolution to a fulminant course. The HAI is sensitive to immunosuppressive therapy. Liver transplantation is indicated in patients with fulminant hepatic failure (encephalopathy) andthose who develop end-stage liver disease.

Hepatite auto-imune tipo 1 em crianças e adolescentes: avaliação da suspensão do tratamento imunossupressor / Type 1 autoimmune hepatitis in children and adolescents: assessment of immunosuppressive treatment withdrawal

OBJETIVO: Avaliar a suspensão do tratamento em crianças e adolescentes com hepatite auto-imune em remissão clínica e laboratorial, por um período mínimo de 24 meses, avaliando o índice de recaída após a suspensão do tratamento. MÉTODO: É um estudo descritivo, retrospectivo e parcialmente prospectivo de 21 crianças e adolescentes com hepatite auto-imune tipo 1, atendidos no Ambulatório de Hepatologia Pediátrica do Hospital das Clínicas da Universidade Federal de Minas Gerais (UFMG), no período de janeiro de 1986 a dezembro de 2001. RESULTADOS: Foram avaliados 54 pacientes, dos quais 21 foram selecionados, sendo 19 do sexo feminino (90,5 por cento), com idade variando de 5,7 a 17,6 anos (mediana de 13,8 anos), tempo médio de seguimento de 5,1±2,4 anos (mediana 4,4 anos) e remissão clínica e laboratorial por um tempo médio de 4,1±1,5 anos (mediana 3,8 anos). Dos 21 pacientes avaliados, 10 (47,6 por cento) ainda apresentavam atividade inflamatória, impossibilitando a suspensão do tratamento, o qual foi interrompido em 11 pacientes (52,4 por cento). Desses, seis pacientes (54,5 por cento) apresentaram reativação da doença, e cinco mantêm remissão clínica e laboratorial, com tempo médio de seguimento de 4±1 anos (mediana 3,9 anos). O intervalo de tempo entre a suspensão do tratamento e a reativação da doença variou de 29 dias a 40,3 meses (mediana 2,2 meses). CONCLUSÕES: Nesse grupo de pacientes com hepatite auto-imune, foi observado alto índice de recaídas (54,5 por cento), que ocorreram com maior freqüência nos primeiros 12 meses pós-suspensão do tratamento, além de grande número de pacientes que apresentou algum grau de atividade inflamatória, apesar do longo tempo de remissão clínico-laboratorial.

Colangitis esclerosante primaria: revisión de 12 años en dos centros de referencia / Primary sclerosing cholangitis: A twelve-year experience

Background:Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by progressive inflammation and fibrosis of the biliary tract, evolving to cirrhosis. It is commonly associated with inflammatory bowel disease (IBD). Aim: To communicate the clinical characteristics of patient with PSC seen in two reference centers. Patients and methods: Review of medical records of patients with PSC confirmed by liver biopsies. The clinical picture, laboratory abnormalities, imaging studies and treatment were recorded. Results: Thirty three patients (aged 16 to 73 years, 64% female) were identified. They corresponded to 1.7% of liver biopsies done between 1991-2003. Clinical presentation was a cholestatic picture in 40%, right upper abdominal pain in 36%, a dysenteric syndrome in 9% and varied symptoms in 15%. Laboratory tests showed cholestasis in 94% and positive anti ANCA, SMA, ANA and AMA antibodies in 28, 18, 15 and 9% of cases, respectively. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiography were diagnostic in 43 and 58% of patients, respectively. There was an association with ulcerative colitis in 12% of cases. Liver biopsies showed grade I PSC in 76% and grade II-III in 6% of patients. It also showed a concomitant chronic hepatitis and primary biliary cirrhosis in 12 and 6% of cases, respectively. Treatment consisted on ursodeoxycholic acid (UDCA) in 45%, UDCA plus 5-aminosalicylic acid derivatives in 12% and UDCA plus immunosuppresors in 12% of patients. Two patients had to be transplanted. Conclusions: PSC is an uncommon cause of chronic liver disease. It is suspected in cholestatic patients and confirmed with a liver biopsy. It can be associated with other autoimmune hepatic and extrahepatic diseases.

Autoimmune hepatitis in children, clinical features and biochemical of Iranian children

There are only a very small number of reports which discuss subtype, sex distribution, clinical features and laboratory characteristics of autoimmune hepatitis in children. The aim of this study was both to define the clinical features, biochemical and histological findings and also to determine the age and sex related distribution of autoimmune hepatitis [AIH]. Data of 30 children presenting with AIH [20 girls and 10 boys] have been analyzed for their clinical, serological, and histological profile. The most common presenting signs or symptoms were jaundice [60%], abdominal mass [23.4%] and constitutional symptoms [weakness, anorexia and paleness] [6.7%]. About 10% of patients had an acute hepatitis like clinical presentation. Twenty two children [73.3%] [15 girls, 7 boys, 2.1:1] had AIH type 1 and 4 patients [13.3%] type 2 due to specific autoantibodies. Four children could not be classified. In liver biopsy, 100% of patients had interface hepatitis and fibrosis with or without cirrhosis were found in 60%. In our cohort the prevalence of AIH was 2:1 in girls. Type 1 was the most frequent diagnosis [73.3%] and was more prevalent in older children. Patients with type 2 were younger. The clinical presentation of AIH in children was unspecific and each type could only be differentiated by the determination of the specific autoantibodies

Historia de las manifestaciones gastrointestinales del lupus eritematoso sistemico / History of the gastrointestinal manifestations in systemic lupus erythematosus

En este articulo revisamos la historia de las manifestaciones gastrointestinales en el Lupus Eritematoso Sistemico desde el siglo XIX hasta nuestros dias, recorriendo cada uno de los organos involucrados en este sistema y haciendo especial mencion de la gastropatia, enteritis, ileitis, sindrome de malabsorcion, vasculitis y vasculopatia intestinal, trombosis mesenterica, pancreatitis, ascitis, peritonitis, hepatitis autoinmune, entre otros

Associação dos antígenos HLA-DR e DQ com a hepatite auto-imune tipos 1 e 2 / Association of HLA-DR and DQ with autoimmune hepatitis types 1 and 2

A susceptibilidade genética à hepatite auto-imune tipo 1 (HAI-1) foi associada aos antígenos de HLA-DR3, DR52 e DR4 em pacientes europeus e norte­ americanos, ao HLA-DR4 no Japão e aos HLA-DR4 e DR13 na América Latina. A predisposição à HAI-1 não foi estudada em outros grupos étnicos e poucos estudos avaliaram pacientes com hepatite auto-imune tipo 2 (HAI-2). O objetivo deste estudo foi investigar a associação dos HLA-DR e DQ em pacientes brasileiros com HAI-1 e HAI-2 e comparar as freqüências desses antígenos com parâmetros clínicos e laboratoriais da doença e com a resposta ao tratamento. A determinação de HLA-DRB e DQB1 foi realizada por PCR-SSP em 143 pacientes e em 126 indivíduos saudáveis. Cento e quinze pacientes apresentaram HAI-1 com reatividade para anticorpo anti-actina (AAA) elou anticorpo antinúcleo (AAN)...