Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology an...Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated,it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine,and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine,but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug,and has good efficacy particularly for patients intolerant to azathioprine,but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine,tacrolimus,everolimus and sirolimus are available. More recently,experience with the anti-tumour necrosis factoralpha infliximab and the anti-CD20 rituximab has been published,with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.展开更多
The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown bu...The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4+ T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to na?ve CD4+ T helper(Th0) cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin(IL) -12,secrete mainly IL-2 and interferon-gamma(IFN-g),which activate macrophages,enhance expression of HLA classⅠ(increasing liver cell vulnerability to a CD8+ T cell cytotoxic attack),and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta(TGF-β) and IL-6 and appear to have an important effector role in inflammation and autoimmunity.Theprocess of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4+CD25+ regulatory T cells,which derive from Th0 in the presence of TGF-β,but in the absence of IL-6.If regulatory mechanisms fail,the autoimmune attack is perpetuated.Over the past three decades different aspects of the above pathogenic scenario have been investigated.In particular,a defect in immunoregulation affecting CD4+CD25+ regulatory T cells(T-regs) has been demonstrated in AIH,particularly at diagnosis or during relapse.Advances in the study of autoreactive T cells have occurred mostly in AIH type 2,since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome.CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6,five of which are also recognized by CD8 T cells.High numbers of IFN-g producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.展开更多
Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis(AIH),autoimmune sclerosing cholangitis(ASC),and de novo AIH after liver transplantation.AIH is divided into two subtypes ...Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis(AIH),autoimmune sclerosing cholangitis(ASC),and de novo AIH after liver transplantation.AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody(SMA/ANA,type 1) or liver kidney microsomal antibody(LKM1,type 2).There is a female predominance in both.LKM1 positive patients tend to present more acutely,at a younger age,and commonly have partial IgA deficiency,while duration of symptoms before diagnosis,clinical signs,family history of autoimmunity,presence of associated autoimmune disorders,response to treatment,and long-term prognosis are similar in both groups.The most common type of paediatric sclerosing cholangitis is ASC.The clinical,biochemical,immunological,and histological presentation of ASC is often indistinguishable from that of AIH type 1.In both,there are high IgG,non-organ specific autoantibodies,and interface hepatitis.Diagnosis is made by cholangiography.Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates,times to normalization of biochemical parameters,and decreased inflammatory activity on follow up liver biopsies.However,the cholangiopathy can progress.There may be evolution from AIH to ASC over the years,despite treatment.De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH,including elevated titres of serum antibodies,hypergammaglobulinaemia,and histological findings of interface hepatitis,bridging fibrosis,and collapse.Like classical AIH,it responds to treatment with prednisolone and azathioprine.De novo AIH postliver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection.Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear.Whatever its etiology,the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.展开更多
Autoimmune hepatitis(AIH)is a T-cell mediated,inflammatory liver disease affecting all ages and characterized by female preponderance,elevated serum transaminase and immunoglobulin G levels,positive circulating autoan...Autoimmune hepatitis(AIH)is a T-cell mediated,inflammatory liver disease affecting all ages and characterized by female preponderance,elevated serum transaminase and immunoglobulin G levels,positive circulating autoantibodies,and presence of interface hepatitis at liver histology.AIH type 1,affecting both adults and children,is defined by positive anti-nuclear and/or antismooth muscle antibodies,while type 2 AIH,affecting mostly children,is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody.While the autoantigens of type 2 AIH are well defined,being the cytochrome P4502D6(CYP2D6)and the formiminotransferase cyclodeaminase(FTCD),in type 1 AIH they remain to be identified.AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages,while DRB1*04 predisposes to late onset disease;AIH-2 is associated with possession of DRB1*07 and DRB1*03.The majority of patients responds well to standard immunosuppressive treatment,based on steroid and azathioprine;second-and third-line drugs should be considered in case of intolerance or insufficient response.This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.展开更多
Autoimmune hepatitis (AIH),a liver disorder affecting both children and adults,is characterized by inflammatory liver histology,elevated transaminase levels,circulating nonorgan-specific autoantibodies,and increased l...Autoimmune hepatitis (AIH),a liver disorder affecting both children and adults,is characterized by inflammatory liver histology,elevated transaminase levels,circulating nonorgan-specific autoantibodies,and increased levels of immunoglobulin G,in the absence of a known etiology.Two types of AIH are recognized according to seropositivity:smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2.AIH type 1 affects both adults and children,while AIH type 2 is mainly a paediatric disease,though it does occasionally affects young adults.AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels.AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine,with symptom free longterm survival for the majority of patients.For those who do not respond to standard treatment,or who are difficult-totreat,mycophenolate mofetil and,in the absence of a response,calcineurin inhibitors should be tried in addition to steroids.The pathogenesis of AIH is not fully understood,although there is mounting evidence that genetic susceptibility,molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack.Liver damage is thought to be mediated primarily by CD4 T-cells,although recent studies support the involvement of diverse populations,including Th17 cells.A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments,such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells,which ultimately aim at restoring tolerance to liver-derived antigens.展开更多
文摘Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated,it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine,and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine,but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug,and has good efficacy particularly for patients intolerant to azathioprine,but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine,tacrolimus,everolimus and sirolimus are available. More recently,experience with the anti-tumour necrosis factoralpha infliximab and the anti-CD20 rituximab has been published,with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
文摘The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4+ T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to na?ve CD4+ T helper(Th0) cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin(IL) -12,secrete mainly IL-2 and interferon-gamma(IFN-g),which activate macrophages,enhance expression of HLA classⅠ(increasing liver cell vulnerability to a CD8+ T cell cytotoxic attack),and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta(TGF-β) and IL-6 and appear to have an important effector role in inflammation and autoimmunity.Theprocess of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4+CD25+ regulatory T cells,which derive from Th0 in the presence of TGF-β,but in the absence of IL-6.If regulatory mechanisms fail,the autoimmune attack is perpetuated.Over the past three decades different aspects of the above pathogenic scenario have been investigated.In particular,a defect in immunoregulation affecting CD4+CD25+ regulatory T cells(T-regs) has been demonstrated in AIH,particularly at diagnosis or during relapse.Advances in the study of autoreactive T cells have occurred mostly in AIH type 2,since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome.CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6,five of which are also recognized by CD8 T cells.High numbers of IFN-g producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.
文摘Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis(AIH),autoimmune sclerosing cholangitis(ASC),and de novo AIH after liver transplantation.AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody(SMA/ANA,type 1) or liver kidney microsomal antibody(LKM1,type 2).There is a female predominance in both.LKM1 positive patients tend to present more acutely,at a younger age,and commonly have partial IgA deficiency,while duration of symptoms before diagnosis,clinical signs,family history of autoimmunity,presence of associated autoimmune disorders,response to treatment,and long-term prognosis are similar in both groups.The most common type of paediatric sclerosing cholangitis is ASC.The clinical,biochemical,immunological,and histological presentation of ASC is often indistinguishable from that of AIH type 1.In both,there are high IgG,non-organ specific autoantibodies,and interface hepatitis.Diagnosis is made by cholangiography.Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates,times to normalization of biochemical parameters,and decreased inflammatory activity on follow up liver biopsies.However,the cholangiopathy can progress.There may be evolution from AIH to ASC over the years,despite treatment.De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH,including elevated titres of serum antibodies,hypergammaglobulinaemia,and histological findings of interface hepatitis,bridging fibrosis,and collapse.Like classical AIH,it responds to treatment with prednisolone and azathioprine.De novo AIH postliver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection.Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear.Whatever its etiology,the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.
基金Open Access funding provided by Universitàdella Svizzera italiana.
文摘Autoimmune hepatitis(AIH)is a T-cell mediated,inflammatory liver disease affecting all ages and characterized by female preponderance,elevated serum transaminase and immunoglobulin G levels,positive circulating autoantibodies,and presence of interface hepatitis at liver histology.AIH type 1,affecting both adults and children,is defined by positive anti-nuclear and/or antismooth muscle antibodies,while type 2 AIH,affecting mostly children,is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody.While the autoantigens of type 2 AIH are well defined,being the cytochrome P4502D6(CYP2D6)and the formiminotransferase cyclodeaminase(FTCD),in type 1 AIH they remain to be identified.AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages,while DRB1*04 predisposes to late onset disease;AIH-2 is associated with possession of DRB1*07 and DRB1*03.The majority of patients responds well to standard immunosuppressive treatment,based on steroid and azathioprine;second-and third-line drugs should be considered in case of intolerance or insufficient response.This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
文摘Autoimmune hepatitis (AIH),a liver disorder affecting both children and adults,is characterized by inflammatory liver histology,elevated transaminase levels,circulating nonorgan-specific autoantibodies,and increased levels of immunoglobulin G,in the absence of a known etiology.Two types of AIH are recognized according to seropositivity:smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2.AIH type 1 affects both adults and children,while AIH type 2 is mainly a paediatric disease,though it does occasionally affects young adults.AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels.AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine,with symptom free longterm survival for the majority of patients.For those who do not respond to standard treatment,or who are difficult-totreat,mycophenolate mofetil and,in the absence of a response,calcineurin inhibitors should be tried in addition to steroids.The pathogenesis of AIH is not fully understood,although there is mounting evidence that genetic susceptibility,molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack.Liver damage is thought to be mediated primarily by CD4 T-cells,although recent studies support the involvement of diverse populations,including Th17 cells.A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments,such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells,which ultimately aim at restoring tolerance to liver-derived antigens.
