Recurrencia de hepatitis autoinmune post trasplante hepático: experiencia de 15 años en el Perú / Autoimmune hepatitis recurrence after liver transplantation: 15 years experience in Peru

Introducción: La recurrencia de la hepatitis autoinmune (HAI) luego del trasplante hepático se presenta entre el 8-68%. En nuestra experiencia las enfermedades autoinmunes del hígado son una indicación principal de trasplante hepático. Objetivo: Determinar la recurrencia de la HAI en 15 años de experiencia y evaluar los factores de riesgo asociados a la recurrencia de HAI. Materiales y métodos: Estudio retrospectivo, descriptivo y trasversal. Desde marzo del 2000 a diciembre del 2015 se realizaron 200 trasplantes en 190 pacientes, algunos de los fueron diagnosticados de cirrosis hepática por HAI. Aquellos pacientes en quienes se detectó una duplicación de los valores normales de aminotranferasa (TGP-TGO <2 VN) en 2 mediciones consecutivas fueron sometidos a biopsia hepática. El diagnostico se realizó por criterio histológico. Resultados: El 19% de trasplantes hepáticos fue por HAI. La edad promedio fue 35 años (con valores extremos de 16 y 64 años); la relación de feminidad fue de 2,2; el subtipo de HAI más frecuente fue el tipo 1 (89%). La recurrencia histológica HAI se evidenció en 11 pacientes (31%). La media de seguimiento fue de 54 meses (con valores extremos de 8 y 169 meses). Conclusiones: En nuestra experiencia la HAI es la indicación más frecuente de trasplante hepático 19%. La recurrencia post trasplante de HAI fue 31%. No se encontró asociación entre el grado de severidad de la actividad histológica en el explante ni en el tipo de HLA en la presentación de la recurrencia.

Introduction: The recurrence of autoimmune hepatitis (HAI) following liver transplantation occurs between 8-68%. In our experience, autoimmune liver diseases are a major indication of liver transplantation. Objective: To determine the recurrence of autoimmune hepatitis in 15 years of experience and to evaluate the risk factors associated with the recurrence of HAI. Materials and methods: Retrospective, descriptive and cross-sectional study. From March 2000 to December 2015; 200 transplants were performed on 190 liver transplants; 36 patients were diagnosed for hepatic cirrhosis by HAI and underwent liver biopsy if transaminase (TGP-TGO >2 ULN) in 2 consecutive measurements. The diagnosis was made by histological criteria. Results: The indication for hepatic transplantation for HAI was 19%. Mean age was 35 years (range 16-64 years) relationship between Sex F / M 2.2, the most common HAI subtype is type 1 (89%). The HAI histological recurrence was 31% (11/36). The mean follow-up was 54 months (range 8-169 months). Conclusions: Autoimmune hepatitis is the most frequent indication of liver transplantation in our experience, accounting for 19%. The recurrence of post-transplant HAI was 31%. No association was found between the degree of severity of histological activity in the explants and the type of HLA in the presentation of the recurrence.

Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice

Abstract Background Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). Methods Wild type (wt) or PPARα-deficient (PPARα−/−) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. Results Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα−/− mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα−/− splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. Conclusion Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.

Hepatitis autoinmune refractaria: ¿cómo escoger el tratamiento de segunda línea o de rescate? / Refractory autoimmune hepatitis: how to choose second-line or rescue therapy?

Autoimmune hepatitis (AIH) is a liver disease of unknown etiology, with a breakdown in peripheral selftolerance against hepatocytes with both genetic and environmental factors involved. It is characterized by an immune mediated liver injury, with detectable autoantibodies, elevated levels of immunoglobulin G and histological criteria including, necroinflammation, lymphoplasmacytic infiltrates and hepatitis interface. It can be asymptomatic or can present as acute hepatitis or liver cirrhosis. Most patients (70-80%) respond to first line therapy (based on steroids ± azathioprine). In those patients not tolerating azatioprine, in steroid resistant, and those with repeated relapses (20-40%), a long-term second line therapy must be considered to avoid progression of liver disease. This last medications include other immunosuppressants like mycophenolate mophetil, calcineurin inhibitors (cyclosporine or tacrolimus), biologic agents (infliximab and rituximab), and other immunosuppressive agents (sirolimus, everolimus), all with good overall clinical results, but not exempt of side effects. Other difficult scenarios include fulminant AIH, end-stage AIH cirrhosis and the management of post-transplant AIH. In this article we will review the literature related to second- line therapy especially of steroid resistant AIH. Future directions in the treatment of HAI should be guided to the individual patient (personalized) and may include cell therapies, such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance

La hepatitis autoinmune (HAI) es una hepatopatía de etiología desconocida, con pérdida de la tolerancia inmune contra los hepatocitos con factores genéticos y ambientales asociados. Se caracteriza por fenómenos de daño inmunológicos, con autoanticuerpos circulantes, una concentración elevada de gammaglobulina sérica y en la biopsia de hígado actividad necroinflamatoria, infiltrados linfoplasmocitarios y daño de interfase. La HAI es una entidad que se puede presentar en forma asintomática, como hepatitis aguda o como cirrosis hepática. El 70-80% de los pacientes responden adecuadamente al tratamiento inmunosupresor de primera línea (corticoides ± azatioprina). En los pacientes que no toleran azatioprina, en los corticorresistentes o en aquellos con recaídas repetidas a pesar de terapia (20-40%), es necesario recurrir a terapias de segunda línea de largo plazo, para evitar la progresión de la hepatopatía. Estas últimas incluyen micofenolato mofetil, inhibidores calcineurínicos (ciclosporina o tacrolimus), agentes biológicos (infliximab y rituximab), y otros fármacos inmunosupresores (sirolimus, everolimus), con resultados alentadores, pero no exentos de efectos colaterales. Otros escenarios complejos incluyen: la HAI de presentación aguda grave y fulminante, la cirrosis terminal autoinmune y la HAI post-trasplante. En este trabajo se revisa la literatura en relación a terapias de segunda línea especialmente en HAI corticoide resistente. El futuro del tratamiento de la HAI va encaminado a una terapia personalizada y que podría incluir terapias celulares como la infusión de células T regulatorias, antígeno específicas y autólogas, para reestablecer los mecanismos de tolerancia inmune hepática.

Estudio comparativo de dos métodos para la determinación de autoanticuerpos en hepatitis autoinmune / Comparative study of two methods in the determination of autoantibodies in autoimmune liver diseases / Estudo comparativo de dois métodos para a determinação de anticorpos no hepatite auto-imune

La hepatitis autoinmune es una inflamación hepatocelular que se caracteriza por diversos autoanticuerpos circulantes. En el presente trabajo se evaluó la concordancia entre los resultados obtenidos por la técnica ELISA y por la técnica de inmunofluorescencia indirecta (IFI) para la determinación de autoanticuerpos en hepatitis autoinmune. Se incluyeron 123 pacientes con hepatitis autoinmune, 91 (74%) del sexo femenino y 32 (26%) de sexomasculino, mayores de 18 años, en los cuales se realizó un estudio comparativo entre ELISA e inmunofluorescencia indirecta para la detección de los anticuerpos antinucleares (78 pacientes), anticuerpos antimitocondriales (84pacientes) y antimicrosoma hepatorrenal (85 pacientes). De acuerdo al valor kappa obtenido se encontró que para el anticuerpo antimicrosoma hepatorrenalel nivel de concordancia fue muy bueno (k=1,0, p<0,001); para el anticuerpoantinuclear el nivel de concordancia fue débil, sin embargo fue significativo(k=0,37, p<0,001) mientras que para el anticuerpo antimitocondrialel nivel de concordancia fue pobre (k=0,05, p<0,476). La determinación del anticuerpo antimicrosoma hepatorrenal fue la prueba con mayor sensibilidad, especificidad y concordancia entre ambas técnicas analizadas y se estableció que la técnica de ELISA para el anticuerpo antimitocondrial solo concuerda con la técnica de inmunofluorescencia indirecta en sujetos con títulos altos.

Autoimmune hepatitis is a hepatocellular inflammation which is characterized by different circulating autoantibodies. In this paper, the correlation between the results obtained by ELISA and indirect immunofluorescence technique for the determination of autoantibodies in autoimmune hepatitis was evaluated. One hundred and twenty-three patients with autoimmune hepatitis, 91 (74%) female and 32 (26%) male, over 18 years were included. In these patients, a comparative study between ELISA and indirect immunofluorescence detection of the antinuclear antibodies (78 patients), anti-mitochondrial antibodies (84 patients) and anti-liver kidney microsome (85 patients) was performed. According to the kappa value obtained, it was found that for anti-liver kidney microsome the level of agreement was very good (k=1.0, p<0.001) for antinuclear antibody, the level of concordance was weak but significant (k=0.37, p<0.001,) meanwhile antimitochondrial antibody level of concordance was poor (k=0.05, p<0.476).The determination of the antibody anti-liver kidney microsome was the test with greater sensitivity, specificity and concordance between the two techniques discussed and it was established that the ELISA technique for antimitochondrial antibody is only in concordance with the indirect immunofluorescence in patients with high titers.

A hepatite autoimune é uma inflamação hepatocelular, que se caracteriza pelos diferentes anticorpos circulantes. Neste trabalho foi avaliada a correlação entre os resultados obtidos através da técnica ELISA e da técnica de imunofluorescência indireta (IFI) para a determinação de auto-anticorpos na hepatite auto-imune. Foram incluídos 123 pacientes com hepatite autoimune, 91 (74%) do sexo feminino e 32 (26%) do sexo masculino, maiores de 18 anos, nos quais foi realizado um estudo comparativo entre ELISA e Imunofluoresência Indireta para a detecção dos anticorpos antinucleares (78 pacientes), anticorpos antimitocondriais (84 pacientes) e antimicrossomal hepatorrenal (85 pacientes). De acordo ao valor kappa obtido, foi encontrado que para o anticorpo antimicrossomal hepatorrenal o nivel de concordância foi muito bom (k=1,0, p<0,001); para o anticorpo antinuclear o nivel de concordância foi fraco, porém foi significativo (k=0,37, p<0,001) enquanto que para o anticorpo antimitocondrial o nivel de concordância foi pobre (k=0,05, p<0,476). A determinação do anticorpo antimicrossomal hepatorrenal foi o teste com maior sensibilidade, especificidade e concordância entre ambas técnicas analisadas e se estabeleceu que a técnica de ELISA, para o anticorpo antimitocondrial, só concorda com a técnica de Imunofluorescência Indireta em sujeitos com títulos altos.

Evolución y respuesta al tratamiento de los pacientes pediátricos diagnósticados con hepatitis autoinmune / Prognosis and Treatment Response in pediatric patients with Autoimmune Hepatitis

Introducción: La Hepatitis Autoinmune (HAI) es una hepatopatía inflamatoria crónica y progresiva, de etiología desconocida, con presencia de autoanticuerpos circulantes e hipergammaglobulinemia. La mayoría de los pacientes responden adecuadamente al tratamiento inmunosupresor, pero si no se instaura se produce destrucción progresiva del parénquima hepático evolucionando a cirrosis e insuficiencia hepática. La interrupción temprana de la terapia puede causar recaídas y aumentar el riesgo de progresión a cirrosis.Objetivo: evaluar la evolución y la respuesta al tratamiento de los pacientes pediátricos con HAI. Materiales y métodos: estudio descriptivo, retrospectivo y transversal de 51 pacientes atendidos en el servicio de Gastroenterología Pediátrica del Hospital JM de los Ríos, de abril de 1996 a septiembre de 2010. De 51 pacientes con diagnóstico de HAI se incluyeron 48 pacientes con más de un año de tratamiento para evaluar evolución y respuesta.Resultados: 79, % de los pacientes presentaron remisión a los 20,4 ± 13,8 meses, 25 % tuvo recaídas. 10/48 (20,8 %) mostraron respuesta incompleta y 38,5 % de ellos no tuvo adherencia al tratamiento (p=0,001). 33/48 (68,8 %) presentaron complicaciones, siendo las más frecuentes: 64,6 % hipertensión portal, 27,2 % osteosporosis/osteopenia y 18,8 % evolucionaron a cirrosis hepática.3 (8,5 %) pacientes presentaron remisión con biopsia hepática normal, luego de aproximadamente 7 años, por lo que se les suspendió el tratamiento, manteniéndose la remisión durante 3,5 años de seguimiento. Dos pacientes requirieron trasplante hepático.Conclusiones: La mayoría de los pacientes respondieron adecuadamente al tratamiento inmunosupresor. La cuarta parte sufrió recaídas. La respuesta incompleta se relacionó significativamente con la falta de adherencia al tratamiento.

Introduction: Autoimmune hepatitis (AIH) is a progressive, chronic disease of unknown etiology, characterized for the presence of circulating autoantibodies and hyper gammaglobulinemia. Most patients respond to immunosuppressive treatment, otherwise, liver parenchimal is progressively destroyed leading to cirrhosis and liver failure. Early withdrawal of therapy might cause relapses and increased risk to cirrhosis.Objective: To assess HAI outcome and treatment response in pediatric patients.Methods: By a retrospective and descriptive analysis we evaluated 51 patients who attended the Pediatric Gastroenterology Department at the “J.M de Los Rios” Children Hospital from April 1996 to September 2010. 48 of these 51 patients have been on immunosuppressive treatment for more than one year.Results: 79.2 % of patients experienced remission at 20.4 ± 13.8 months, 25 % relapsed. 10/48 (20.8 %) showed incomplete response and 38.5 % had no adherence to treatment (p = 0.001). 33/48 (68.8 %) had complications, being the most frequent portal hypertension 64.6 %, following by osteoporosis and osteopenia 27,2 %, and 18.8 % developed cirrhosis.3 (8.5 %) patients had remission with normal liver biopsy after approximately 7 years, so treatment was discontinued, maintaining remission for 3.5 years. Two patients required liver transplantation.Conclusions: Most patients responded well to immunosuppressive therapy. 25 % suffered relapses. The incomplete response was significantly associated to non-adherence to treatment.

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.

Brucellosis as trigger for autoimmune hepatitis in susceptible individual

Autoimmune hepatitis [AIH] is a rare chronic liver disease of unknown etiology, characterized by hypergammaglobulinemia, characteristic autoantibodies, and a favorable response to immunosuppressive treatment. Strong circumstantial evidences denoted that there is quite long list of environmental factors such as [food additives and drugs], viruses and toxins which play an important role in precipitating this disease. Brucellosis is endemic in Iraq. It may involve any organ in the body. Liver is frequently involved. Doxycycline used for treatment occasionally may lead to hepatotoxicity. The aim of the study is to show the relationship between brucellosis, AIH, and hepatotoxicity of doxycycline. The study was performed on 2 Iraqi patients with brucellosis, attending the teaching hospital for gastroenterology and liver disease in the period between November 2003 and July 2004. Brucella were studied by Rose Bengal test and confirmed by indirect immuno florescence assay [IIF]. Anti-SLA/LP Abs was detected in 2 patients with brucellosis. Brucellosis or doxycycline is a trigger of AIH

Liver involvement in celiac disease.

Celiac disease may present as a cryptogenic liver disorder being found in 5-10 % of patients with a persistent and cryptogenetic elevation of serum aminotransferase activity. In fact, a wide spectrum of liver injuries in children and adults may be related to CD and in particular: (1) a mild parenchymal damage characterised by absence of any clinical sign or symptom suggesting a chronic liver disease and by non-specific histological changes reversible on a gluten-free diet; (2) a chronic inflammatory liver injury of autoimmune mechanism, including autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis, that may lead to fibrosis and cirrhosis, generally unaffected by gluten withdrawal and necessitating an immunosuppressive treatment; (3) a severe liver failure potentially treatable by a gluten-free diet. Such different types of liver injuries may represent a spectrum of a same disorder where individual factors, such as genetic predisposition, precocity and duration of exposure to gluten may influence the reversibility of liver damage. A rigorous cross-checking for a asymptomatic liver damage in CD individuals and conversely, for CD in any cryptogenic liver disorder including end-stage liver failure is recommended.

Primary biliary cirrhosis and autoimmune hepatitis switch over: report of 2 cases.

Overlap syndrome in Autoimmune liver disease is not unusual but the switch over from one type of autoimmune liver disease to another is not well recognized. We report 2 cases of primary biliary cirrhosis (PBC) who with time, crossed over to autoimmune hepatitis (AIH). Recognition of such switch over from PBC to AIH is important for appropriate change in management of the patients.

A Case of Cholestatic Autoimmune Hepatitis and Acute Liver Failure: an Unusual Hepatic Manifestation of Mixed Connective Tissue Disease and Sjogren's Syndrome

Although hepatomegaly is reported to occur occasionally in patients with mixed connective tissue disease (MCTD) or Sjogren's syndrome (SS), autoimmune liver diseases such as primary biliary cirrhosis, sclerosing cholangitis, and autoimmune hepatitis in association with MCTD or SS have rarely been described. We report a case of severe cholestatic autoimmune hepatitis presenting with acute liver failure in a 40-yr-old female patient suffering from MCTD and SS. The diagnosis of MCTD and SS was made at the age of 38. The patient presented severe jaundice and elevation of conjugated bilirubin. The patient denied alcohol and drug use and had no evidence of viral hepatitis. On the 8th day of her hospitalization, the patient developed grade III hepatic encephalopathy. She was diagnosed as autoimmune hepatitis presenting with acute liver failure based on clinical features, positive FANA and anti-smooth muscle antibodies, negative anti-mitochondrial antibodies, high titers of serum globulin, liver biopsy findings, and a good response to corticosteroid therapy, The patient was managed with prednisolone and the clinical symptoms, liver function test results, and liver biopsy findings showed much improvement after steroid therapy.

Hepatitis autouinmune en niños. Presentación inicial como falla hepática fulminante / Autoimmune hepatitis in children. Initial presentation of fulminant hepatic failure

There are few cases reported of autoinmune hepatitis (AIH) tipe 2 presenting as fulminant hepatic failure (FHF) in children. The purpose of this study was to report three girls with AIH type 2 that presented as FHF. METHODS: Over a period of 12 years, 123 patients with AIH diagnosed based on international criteria, 9 (7 per cent were type 2.3 of them presented as FHF. Other etiologies (viral, metabolic and toxic) were ruled out. The treatment was started with prednisone (2 mg-kg-day) and azathioprine (2 mg-kg-day). EVOLUTION: Patients 1 and 3 died while waiting for liver transplant (LT) at 72 and 48 hours after initiating medical treatment. Patient 2 underwent LT3 days after starting treatment, with excellent evolution at 3 years and 7 months of follow up. CONCLUSIONS: 1--AIH type 2 was very infrequent in our group. 2--33 per cent of cases had initial presentation as FHF. 3--The course of the disease was aggressive, not responding to immunosupreessive therapy. The evolution was unfavorable in all patients. 4--LT is an alternative treatment for this severe disease.

Circulating immune complex in murine autoimmune hepatitis.

High level of circulating immune complexes (CIC) in the serum has been reported in different forms of hepatitis particularly in complicated cases of viral hepatitis due to hepatitis B virus (HBV) infection. In this study CIC level in experimental autoimmune hepatitis were assessed by detection of polyethylene glycol (PEG) index. The sera of mice with established autoimmune hepatitis (EAH) confirmed by histopathological study showed higher PEG index (C57BL/6 mice: 34.56 +/- 6.28 and C3H mice: 31.95 +/- 28.99). The control healthy mice showed lower PEG index (C57BL/6 mice: 19.48 +/- 6.85 and C3H mice: 21.27 +/- 6.1). The high level of PEG index in EAH was found statistically significant. The role of CIC in the development of autoimmune hepatitis is discussed.