RESUMO
BACKGROUND: Advances in autoimmune hepatitis that transform current concepts of pathogenesis and management can be anticipated as products of ongoing investigations driven by unmet clinical needs and an evolving biotechnology. AIM: To describe the advances that are likely to become transformative in autoimmune hepatitis, based on the direction of current investigations. METHODS: Pertinent abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and a secondary bibliography was developed. The discovery process was repeated, and a tertiary bibliography was identified. The number of abstracts reviewed was 2830, and the number of full-length articles reviewed exceeded 150. RESULTS: Risk-laden allelic variants outside the major histocompatibility complex (rs3184504, r36000782) are being identified by genome-wide association studies, and their gene products are potential therapeutic targets. Epigenetic changes associated with environmental cues can enhance the transcriptional activity of genes, and chromatin re-structuring and antagonists of noncoding molecules of ribonucleic acid are feasible interventions. The intestinal microbiome is a discovery field for microbial products and activated immune cells that may translocate to the periphery and respond to manipulation. Epidemiological studies and controlled interview-based surveys may implicate environmental and xenobiotic factors that warrant evidence-based changes in lifestyle, and site-directed molecular and cellular interventions promise to change the paradigm of treatment from one of blanket immunosuppression. CONCLUSIONS: Advances in genetics, epigenetics, pathophysiology, epidemiology, and site-directed molecular and cellular interventions constitute the next generation of transformative advances in autoimmune hepatitis.
Assuntos
Microbioma Gastrointestinal , Hepatite Autoimune/terapia , Estudo de Associação Genômica Ampla , Hepatite Autoimune/fisiopatologia , HumanosRESUMO
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Aloenxertos , Humanos , Relatório de PesquisaRESUMO
BACKGROUND: Chemokines contribute to the pathogenesis of autoimmune hepatitis by directing the migration and positioning of inflammatory and immune cells within the liver. AIM: Describe the liver-infiltrating effector cell populations in autoimmune hepatitis, indicate the chemokines that influence their migration, describe the role of chemokines in hepatic fibrosis and identify chemokine-directed treatment opportunities. METHODS: Studies cited in Pub Med from 1972 to 2014 for autoimmune hepatitis, chemokines in liver disease, pathogenesis of autoimmune hepatitis and chemokine therapy were selected. RESULTS: T helper type 17 lymphocytes expressing CXCR3 and CCR6 are attracted to the liver by the secretion of CXCL9, CXCL10 and CXCL11. These cells recruit pro-inflammatory T helper type 1 lymphocytes expressing CXCR3 and CCR5 by secreting CXCL10. Resident natural killer T cells expressing CXCR6 migrate in response to the local secretion of CXCL16, and they modulate the inflammatory response. T helper type 2 lymphocytes expressing CCR4 are attracted by CCL17 and CCL22, and they dampen the expansion of pro-inflammatory cells. Regulatory T cells expressing CXCR3 are attracted by the secretion of CXCL9, and they help dampen the pro-inflammatory responses. CCL2, CCL3, CCL5, CXCL4, CXCL10 and CXCL16 promote fibrosis by activating or attracting hepatic stellate cells, and CX3CL1 may prevent fibrosis by affecting the apoptosis of monocytes. CONCLUSIONS: Chemokines are requisites for mobilising, directing and positioning the effector cells in immune-mediated liver disease. They are feasible therapeutic targets in autoimmune hepatitis, and the evaluation of monoclonal antibodies that neutralise the pro-inflammatory ligands or designer peptides that block receptor activity are investigational opportunities.
Assuntos
Quimiocinas/imunologia , Hepatite Autoimune/imunologia , Animais , Hepatite Autoimune/tratamento farmacológico , Humanos , Receptores de Quimiocinas/imunologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. AIM: To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. METHODS: Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. RESULTS: The frequency of a treatment-free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo-antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response. CONCLUSIONS: Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.
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Glucocorticoides/administração & dosagem , Hepatite Autoimune/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Feminino , Glucocorticoides/uso terapêutico , Hepatite Autoimune/fisiopatologia , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática , Masculino , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM: To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS: Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS: Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS: The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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Hepatite Autoimune/complicações , Cirrose Hepática/prevenção & controle , Animais , Progressão da Doença , Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Transplante de Fígado/estatística & dados numéricosRESUMO
Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and its frequency is expected to increase. The possibility of identifying early stage curative cancer has supported the recommendation of surveillance by hepatic ultrasonography every 6 months in individuals with an annual incidence of cancer that exceeds 1.5%. Computerized tomography or magnetic resonance imaging is diagnostic if contrast uptake within the nodule is demonstrated in the arterial stage and washout is evident. Liver tissue examination is warranted in indeterminate nodules larger than 1 cm, and stromal invasion is the pathological hallmark. The Barcelona Clinic Liver Cancer staging system indicates the most appropriate evidence-based therapy. Liver resection is preferred for nodules <2 cm in the absence of portal hypertension or hyperbilirubinemia, and liver transplantation is the choice in patients without cirrhosis or with Child-Pugh A or B cirrhosis who have portal hypertension or hyperbilirubinemia. Radiofrequency ablation should be performed if transplantation is not an option and the total number of nodules is less than 3 and all are smaller than 3 cm. Intermediate or advanced stage cancer, defined by multinodularity, macrovascular invasion or extrahepatic spread, should be palliated by transarterial chemoembolization, treatment with sorafenib, or symptomatic care. Early referral to a tertiary care center is encouraged if there are deficiencies in diagnostic or therapeutic expertise or resources. In regions with limited resources, strong preventive measures must be instituted and at least hepatic resection or tumor ablation must be developed.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Algoritmos , Detecção Precoce de Câncer , Humanos , Transplante de Fígado , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Fatores de RiscoRESUMO
BACKGROUND: Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS: To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS: Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS: Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS: Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
Assuntos
Hepatite Autoimune/tratamento farmacológico , Imunossupressores/uso terapêutico , Conferências de Consenso como Assunto , Hepatite Autoimune/diagnóstico , Humanos , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. AIM: To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences. METHODS: Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. RESULTS: Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. CONCLUSIONS: Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.
Assuntos
Hepatite Autoimune/tratamento farmacológico , Imunossupressores/uso terapêutico , Fatores Etários , Humanos , Recidiva , Índice de Gravidade de Doença , Falha de TratamentoRESUMO
Autoimmune hepatitis has diverse clinical presentations which complicate its diagnosis and adverse outcomes which demand new treatments. The aims of this review are to indicate the progress that has been made in solving these problems and to illuminate the pathway for additional solutions. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into a personal library spanning 31 years. Two diagnostic scoring systems with complementary virtues have been developed that are useful in evaluating patients with confusing features. Acute severe and fulminant presentations require prompt corticosteroid therapy, and coincidental bile duct changes and centrilobular zone 3 necrosis on histological examination do not discount the diagnosis. Cholangio-graphic changes may be present in children and adults with the disease, and antibodies to soluble liver antigen have prognostic value. Autoimmune hepatitis must be considered in patients without autoantibodies and with graft dysfunction after liver transplantation. Asymptomatic patients may not require immediate treatment, and the Model of End Stage Liver Disease identifies problematic patients early. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine can be used as frontline treatment in select patients. Progress has been made in the diagnosis and treatment of autoimmune hepatitis, but more work must be done. Multicenter clinical trials are essential before the incorporation of new drugs into the treatment algorithm.
Assuntos
Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Biomarcadores/sangue , Feminino , Hepatite Autoimune/patologia , Humanos , Masculino , Gravidez , Complicações na Gravidez/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
Genome scanning studies suggest an important role for genes outside the major histocompatibility complex in autoimmunity. Key candidates are those genes involved in immune regulation and preservation of immune homeostasis, including the genes involved in apoptosis. Our aim was to determine the association between the Fas gene polymorphism at position -670 and susceptibility, clinical expression, and outcome in type 1 autoimmune hepatitis (AIH). An adenosine to guanine single nucleotide polymorphism in the Fas gene (TNFRSF6) promoter was assessed in 149 well-characterized Caucasoid patients and 172 matched controls. Patients and normal subjects had the similar TNFRSF6-670 allele and genotype frequencies. Serum aspartate aminotransferase (510 +/- 77 vs 283 +/- 53 U/l), gamma-globulin (3.3 +/- 0.2 vs 2.6 +/- 0.2 g/dl), and immunoglobulin G (2976 +/- 223 vs 2324 +/- 203 mg/dl) levels were higher in patients with the guanine/guanine genotype than in those with the adenosine/adenosine genotype. Cirrhosis at presentation was more common in patients with the adenosine/adenosine or adenosine/guanine genotypes than in those with the guanine/guanine genotype (29% vs 6%). Polymorphism of the Fas gene at position -670 does not influence susceptibility to AIH, but may affect the early development of cirrhosis.
Assuntos
Predisposição Genética para Doença , Hepatite Autoimune/genética , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Receptor fas/genética , Alelos , Feminino , Frequência do Gene , Genótipo , Hepatite Autoimune/sangue , Hepatite Autoimune/complicações , Hepatite Autoimune/patologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , População BrancaRESUMO
The diagnostic criteria for autoimmune hepatitis have been codified, and a scoring system can quantify the strength of the diagnosis. Centrilobular (zone 3) necrosis signifies acute disease, and severe acute and fulminant presentations of autoimmune hepatitis are recognized. The absence of symptoms at presentation may identify some patients who do not require treatment, but therapeutic decisions must be based on disease activity not symptoms, especially since 26-70% of asymptomatic patients become symptomatic. Elderly patients have more advanced disease at presentation, but they respond well to treatment. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1 have prognostic value. Molecular mimicry between viral and self-antigens is the likely basis for the autoimmune response. Susceptibility alleles optimize antigen presentation. Polymorphisms influence immunocyte activation, counter-regulatory actions within the cytokine milieu, and apoptotic pathways for hepatocyte and immunocyte death. Perturbations in the populations of T regulatory cells and natural killer T cells disrupt immune homeostasis. Cyclosporine, mycophenolate mofetil, and budesonide afford new treatment opportunities, and molecular interventions at critical pathogenic pathways are feasible, especially within the cytokine network. Confident animal models of the human disease and a collaborative network of clinical investigators are the requisites for progress.
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Hepatite Autoimune , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Hepatite Autoimune/imunologia , HumanosRESUMO
Autoimmune hepatitis has a global occurrence and diverse manifestations. Patients are frequently asymptomatic (34%), and an acute, even fulminant, presentation is possible. Concurrent immune disorders may obscure the liver disease, and perivenular (Rappaport zone 3) necrosis is within the histological spectrum. Clinical phenotypes and outcomes vary among different ethnic groups, and genetic factors strongly affect susceptibility. Non-disease specific autoimmune modifiers include female gender and gene polymorphisms that affect immunocyte activation and differentiation. Antibodies to soluble liver antigen/liver pancreas may have prognostic importance and reflect a genetic propensity for severe disease. Subtypes based on serological profiles do not have distinctive outcomes or therapies. Variant forms include patients with bile duct injury or loss, absence of conventional serological markers, abnormal cholangiograms, or coincidental hepatitis C. Treatment is empiric and based on the predominant manifestations (hepatitic, cholestatic, or viral). New treatment strategies must be strengthened by predictive indices that accurately forecast individual differences in disease outcome. Drugs with site-specific actions on immunocyte activation and proliferation (cyclosporine, tacrolimus and myco-phenolate mofetil) must be assessed by clinical trial, and site-specific molecular interventions (blocking peptides, recombinant immune modulators, T cell vaccination, oral tolerance, gene silencing and gene therapy) require confident experimental animal models for evaluation. Better prognostic indices, new immunosuppressive agents, and site-specific molecular interventions promise to improve care.
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Hepatite Autoimune/diagnóstico , Hepatite Autoimune/terapia , Antígenos HLA-DR , Hepatite Autoimune/sangue , Hepatite Autoimune/complicações , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Humanos , FenótipoRESUMO
Anti-mitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cirrhosis (PBC), but may be missing in a proportion of these patients. We assessed sensitivity and specificity of the currently available techniques for AMA detection in a large series of PBC patients and controls, and analysed their clinical and immunological features according to the AMA status. By indirect immunofluorescence on rat tissue sections and HEp-2 cells, Western immunoblot with bovine submitochondrial particles, and two ELISAs with AMA-specific recombinant proteins, we evaluated the presence of AMA in 127 PBC patients, 166 patients with type 1 autoimmune hepatitis and 100 with non alcoholic fatty liver disease. In PBC patients Western immunoblot detects AMA significantly more often than indirect immunofluorescence on HEp-2 cells (85%versus 72%, P = 0.02) or rodent tissue sections (71%, P = 0.01); both ELISAs are only slightly less sensitive than Western immunoblot (81% and 78%). Ten patients with non alcoholic fatty liver disease were AMA-positive by indirect immunofluorescence, but none recognized AMA-specific epitopes in Western immunoblot or in ELISAs. Twelve patients with type 1 autoimmune hepatitis were AMA-positive by indirect immunofluorescence, but only 6 (3.6%) reacted by Western immunoblot and ELISAs. Western immunoblot or ELISA should be regarded as first-line assay for the detection of AMA. Up to 15% of PBC patients are consistently AMA-negative, yet they share the same clinical, biochemical and histological features of AMA-positive PBC. Detection of AMA in type 1 autoimmune hepatitis might identify a subset of patients at risk of developing a hepatitic/cholestatic syndrome.
Assuntos
Autoanticorpos/sangue , Cirrose Hepática Biliar/diagnóstico , Mitocôndrias/imunologia , Adulto , Idoso , Biomarcadores/sangue , Western Blotting/métodos , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática/métodos , Reações Falso-Negativas , Feminino , Técnica Indireta de Fluorescência para Anticorpo/métodos , Hepatite Autoimune/diagnóstico , Humanos , Cirrose Hepática Biliar/imunologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Antibodies to soluble liver antigen/liver pancreas (SLA/LP) are specific markers of autoimmune hepatitis. Their target antigen has recently been cloned. AIMS: To establish standardised immunoassays using the recombinant antigen, and to assess the frequency and significance of seropositivity in patients from different countries. METHODS: An enzyme linked immunoassay was developed using purified recombinant antigen and validated by testing sera from 200 healthy blood donors and 1026 patients with various liver and non-liver diseases. The assay was then applied to 454 sera from 419 patients with autoimmune hepatitis from different countries. All sera were also tested by inhibition immunoassay and western blot. RESULTS: Antibodies were reliably detected by the recombinant immunoassay and occurred exclusively in patients with autoimmune liver disease. Twenty three of 149 patients from the USA (15%), 23/132 from Brazil (17%), 21/108 from Germany (19%), and 2/30 from Japan (7%) were seropositive. Clinical features at presentation were similar between seropositive and seronegative patients. However, relapse after corticosteroid withdrawal or during maintenance therapy occurred more commonly in seropositive patients. CONCLUSIONS: Antibodies to SLA/LP can be reliably detected by these standardised immunoassays based on recombinant antigen. Antibodies to SLA/LP occur with similar frequencies in different geographical regions, races, and age groups, and are of exquisite diagnostic specificity. Whether SLA/LP positive patients represent a clinically distinct subgroup remains to be determined; relapse during treatment reduction appeared to be more common in the SLA/LP group.
Assuntos
Anticorpos Monoclonais/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Hepatite Autoimune/diagnóstico , Antígenos de Histocompatibilidade Classe I , Adolescente , Adulto , Anticorpos Monoclonais/imunologia , Biomarcadores/sangue , Brasil , Criança , Pré-Escolar , Feminino , Alemanha , Hepatite Autoimune/terapia , Antígenos de Histocompatibilidade Classe II , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Proteínas Recombinantes , Recidiva , Sensibilidade e Especificidade , Resultado do Tratamento , Estados UnidosRESUMO
Bile duct changes are atypical of autoimmune hepatitis. Our aims were to assess the frequency and significance of these changes in classical disease. Liver biopsy specimens were reviewed under code from 84 patients who satisfied international scoring criteria for autoimmune hepatitis, and the findings were correlated with clinical features and outcome. Twenty patients (24%) had biliary changes, including 6 with destructive cholangitis, 4 with ductopenia, and 10 with nondestructive cholangitis. Patients with and without bile duct changes had similar laboratory findings. Diagnostic scores for autoimmune hepatitis were lower in patients with bile duct changes (16.6 +/- 0.6 vs. 19.1 +/- 0.2, P <.0001). The frequencies of scores sufficient for a definite (80% vs. 97%, P =.03) or probable diagnosis (20% vs. 3%, P =.03) were also less in this group. Patients with destructive cholangitis and/or ductopenia responded as well to therapy as patients with nondestructive cholangitis, and outcomes in each group were similar to those of patients without biliary changes. We concluded that biliary changes can occur in classic autoimmune hepatitis, and they are not associated with distinctive clinical features or treatment response. They may be coincidental findings associated with classic disease or weak expressions of a variant syndrome. In the absence of a cholestatic clinical syndrome, they do not compel a different management strategy.
Assuntos
Ductos Biliares/patologia , Hepatite Autoimune/patologia , Adolescente , Adulto , Idoso , Colangite/patologia , Feminino , Hepatite Autoimune/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.