Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pat...Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pathogenesis of AIH.Immunosuppressive therapy is the mainstay of treatment;however,10%–25%of patients with AIH may not respond to primary therapy.Those patients are often salvaged with second-and third-line immunosuppressive therapy.Workup for other concomitant diseases should be done for patients who fail to respond to primary immunosuppressive therapy.Concurrent metabolic dysfunction-asso-ciated steatotic liver disease,alcohol-related liver disease,overlap syndrome(AIH with primary biliary cholangitis or sclerosing cholangitis),chronic hepatitis B virus,hepatitis C virus,and human immunodeficiency virus infection should be ruled out in such cases.Targeting the concomitant etiology may lead to resolution of the clinical symptoms and induce biochemical and histological remission.Isolated AIH without other etiologies for liver injury should be managed with a higher dose of steroids,azathioprine,or other immunosuppressive agents.Second-and third-line immunosuppressive agents include mycophenolate mofetil,cyclosporine,tacrolimus,infliximab,and rituximab.Patients with AIH may present with acute severe AIH(AS-AIH)and AIH-related acute on chronic liver failure,and they often require liver transplantation.The terms refractory or difficult-to-treat AIH have been used interchangeably and have no distinct definition.Difficult-to-treat AIH includes patients with intolerable side effects,fulminant disease(AIH with acute on chronic liver failure and AS-AIH),AIH in pregnancy,and HIV infection.Patients who fail to respond to standard first-line immunosuppressive therapy should be classified as refractory AIH.This review addresses the issues in the management of difficult-to-treat AIH with recent advances in pharmacological management.展开更多
BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recen...BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recently been explored for these difficult cases.AIM To assess the efficacy and safety of biologics in AIH,focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission.METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH.The primary focus was on serological improvement and histological remission.The secondary focus was on assessing therapy safety and additional outcomes.A standardized search command was applied to MEDLINE,EMBASE,and Cochrane Library databases to identify relevant studies.Inclusion criteria encompassed adult AIH patients treated with biologics.Data were analyzed based on demographics,prior treatments,and therapy-related outcomes.A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence.RESULTS A total of 352 studies were reviewed,with 30 selected for detailed analysis.Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies.Rituximab demonstrated high efficacy,with 41 out of 45 patients showing significant improvement across six studies.Basiliximab was assessed in a single study,where the sole patient treated experienced a beneficial outcome.Additionally,a notable number of AIH cases were induced by anti-tumor necrosis factor(TNF)medications,including 16 cases associated with infliximab and four cases with adalimumab.All these cases showed improvement upon withdrawal of the biologic agent.CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH,demonstrating significant improvements in clinical outcomes and liver function.However,the variability in patient responses to different therapies highlights the need for personalized treatment strategies.The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition.These findings support the incorporation of biologic agents into AIH treatment protocols,particularly for patients who do not respond to conventional therapies.展开更多
To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosu...To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosuppressive therapy,utilizing corticosteroids and azathioprine(Imuran),which result in clinical and histological im-provement among 60%AIH patients[1,2].The diagnosis of AIH requires a combination of clinical,bio-chemical,and histological findings.The first diagnostic system was established in 1993[3],revised in 1999[4],and then a simplified criterion was proposed[5].Liver histology plays an important role in the scoring systems of AIH diagnosis and is essential to make an accurate diagnosis.Due to the lack of obvious symptoms in the early stage,about 30%patients have already progressed to cirrho-sis by the time of diagnosis[6].展开更多
BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performanc...BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.展开更多
In this article,we comment on the article by Peta et al.This study evaluates the diagnostic performance of FibroTest-Actitest,transient elastography,and the fibrosis-4 index against a histological reference.Using the ...In this article,we comment on the article by Peta et al.This study evaluates the diagnostic performance of FibroTest-Actitest,transient elastography,and the fibrosis-4 index against a histological reference.Using the Obuchowski measure,the authors demonstrate that FibroTest and vibration-controlled transient elastography outperform the fibrosis-4 index in detecting fibrosis.Additionally,Actitest offers superior estimation of inflammatory activity compared to conventional biomarkers.Assessing liver fibrosis is crucial for managing autoimmune hepatitis(AIH),yet reliance on invasive liver biopsy remains higher than in other liver diseases.This is partly due to more complex diagnostic criteria for AIH,the lack of standardized scoring for non-invasive testing,and the presence of inflammation,which can lead to falsely elevated results with non-invasive tests.A Bayesian latent class model further supports the reliability of these non-invasive tests,highlighting their potential to complement biopsy,particularly for longterm disease monitoring.These findings underscore the importance of noninvasive diagnostics in optimizing AIH management.展开更多
Refractory autoimmune hepatitis(AIH)is defined as intolerance of or unresponsiveness to standard immunosuppression and occurs in 10%-20%of children with AIH.Lack of response or slower than expected response to inducti...Refractory autoimmune hepatitis(AIH)is defined as intolerance of or unresponsiveness to standard immunosuppression and occurs in 10%-20%of children with AIH.Lack of response or slower than expected response to induction of remission with steroids,despite good compliance,might be the first clue to refractory AIH.Refractoriness to treatment is associated with an 11.7 times higher risk for liver transplantation or death due to liver disease.The first and foremost consideration for the management is to assess compliance with treatment.It is then important to re-evaluate the diagnosis,assess alternative aetiologies which can mimic the clinical,serological,and histological features of AIH,and address the presence of extra-hepatic co-morbidities.It is important to consider the specific clinical situations,previous therapy,and prior adverse effects before deciding on the most appropriate treatment regimen in refractory AIH.Consideration also should be given to compliance with previous therapy,need for drug level monitoring,growth potential,available formulations,route of administration of medication,and children’s and families’preferences before deciding on the therapy.Treatment should be decided and monitored only in specialized hepatology centers.展开更多
BACKGROUND Hepatitis D virus-hepatitis B virus(HDV-HBV)co-infection accelerates liver disease progression and increases the risk of hepatocellular carcinoma,but the immunopathogenic mechanism of its combination with a...BACKGROUND Hepatitis D virus-hepatitis B virus(HDV-HBV)co-infection accelerates liver disease progression and increases the risk of hepatocellular carcinoma,but the immunopathogenic mechanism of its combination with autoimmune hepatitis(AIH)has not been clarified.This study reveals for the first time that HDV may induce AIH through abnormalities in immunoregulation in two specific cases.This is the first report of HDV-HBV co-infected patients who did not receive interferon therapy and achieved serological conversion and histological remission by combining antiviral(entecavir)with immunosuppression(prednisone+azathioprine)therapy,providing new evidence of the mechanism of this complex disease.CASE SUMMARY A 40-year-old female developed malaise and jaundice with an alanine aminotransferase/aspartate aminotransferase>20 upper limit of normal(ULN),total bilirubin:97.20μmol/L,immunoglobulin G(IgG)47.1 g/L(>3×ULN),HDV RNA 1.6×10^(7)copies/mL and liver biopsy showed G3S4.Tenofovir alafenamide combined with prednisone and azathioprine was administered,and three months later the Child-Turcotte-Pugh class C was reduced to class B and IgG decreased to 13.62 g/L.Another 58-year-old male complained of pain in the liver area,antinuclear antibody was 1:320,IgG 22.6 g/L(>1.3×ULN),and liver biopsy showed G2S3.Entecavir was administered in combination with prednisone and azathioprine,and after 3 months,liver function returned to normal,and IgG reduced to 14.22 g/L.CONCLUSION Patients with HDV-HBV co-infection combined with AIH can achieve clinical remission following combination therapy,and the study of immunomodulatory mechanisms should be emphasized.展开更多
BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primar...BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.展开更多
BACKGROUND Autoimmune hepatitis(AIH)is characterized by inflammation,hepatocyte necrosis,autoantibodies,and elevated serum globulin levels.It can present at any age,with peaks reported at 30 years and after 60 years.N...BACKGROUND Autoimmune hepatitis(AIH)is characterized by inflammation,hepatocyte necrosis,autoantibodies,and elevated serum globulin levels.It can present at any age,with peaks reported at 30 years and after 60 years.No national studies have evaluated the impact of age at diagnosis on AIH presentation and outcomes.AIM To compare the presentation and progression of AIH in patients diagnosed before and after the age of 60 years.METHODS This cross-sectional analytical study included biopsy-confirmed AIH patients with at least one year of follow-up at Hospital Clínico Universidad de Chile,Santiago,Chile.Demographic,clinical,laboratory,and treatment response variables were analyzed.Group comparisons(diagnosis before or after 60 years)were performed using theχ2 test for qualitative variables and the Mann-Whitney test for quantitative variables(significance P<0.05).RESULTS Ninety-seven AIH patients were included;85%were female,with a median age of 53 years(range 18-83 years).Forty-one percent were diagnosed after the age of 60.Younger patients exhibited more jaundice at diagnosis(75%vs 44%,P=0.02)and higher aminotransferases levels(median alanine aminotransferase 998 IU/mL vs 334 IU/mL,P=0.0002).In contrast,at diagnosis,ascites was more prevalent in patients over 60(13%vs 2%,P=0.028),and advanced fibrosis(F3-F4)was more frequent in this group(68%vs 41%,P=0.020).Biochemical response at six months was similar between groups,despite lower corticosteroid doses being administered to patients over 60 years.CONCLUSION AIH in patients over 60 presented with less jaundice,lower aminotransferases levels,greater fibrosis,and more ascites.Biochemical response was similar independently of age and despite lower prednisone doses administered in patients over 60 years.展开更多
Objective:To explore the molecular mechanism and action pathways of Wumei Pill in the treatment of autoimmune hepatitis(AIH)using network pharmacology and molecular docking methods.Methods:The active components and ta...Objective:To explore the molecular mechanism and action pathways of Wumei Pill in the treatment of autoimmune hepatitis(AIH)using network pharmacology and molecular docking methods.Methods:The active components and targets of Wumei Pill,as well as AIH-related disease targets,were screened through the TCMSP,GeneCards,OMIM,and Disgenet databases.Cytoscape 3.9.1 was used to construct a series of topological networks,followed by Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis and Gene Ontology(GO)enrichment analysis.Molecular docking and visualization were performed using AutoDockTools 1.5.7 and PyMOL 2.4.0.Results:A total of 124 active components of Wumei Pill,877 drug targets,1130 disease targets,and 64 overlapping targets were obtained.GO enrichment analysis yielded 82 biological processes,4 cellular components,and 19 molecular functions.KEGG pathway enrichment analysis identified 21 signaling pathways.Conclusion:Wumei Pill can act on targets such as Tumor Necrosis Factor(TNF),Caspase 3(CASP3),C-X-C Motif Chemokine Ligand 8(CXCL8),Nuclear Factor Kappa B Subunit 1(NFKB1),and Transforming Growth Factor Beta 1(TGFB1)through active components including girinimbine and(R)-tetrahydroberberine.It further regulates inflammation and apoptosis-related pathways such as tumorrelated signaling pathways and Th17 cell differentiation pathway to treat AIH.This study provides a theoretical basis for in-depth research on the mechanism of Wumei Pill in the treatment of AIH and the development of therapeutic drugs.展开更多
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels.Liver transplantation may be required for patients with acute ...Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels.Liver transplantation may be required for patients with acute liver failure,decompensated cirrhosis,and hepatocellular carcinoma.Recurrence is defined as development of the same disease in the allograft following liver transplantation.Autoimmune hepatitis recurs in 36%-68%of the recipients 5 years after liver transplantation.De novo autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis.Diagnostic work up for recurrent and de novo autoimmune hepatitis is similar to the diagnosis of the original disease,and it is usually difficult.Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and de novo autoimmune hepatitis.Early diagnosis and treatment are vital for patient prognosis because de novo autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.展开更多
Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH inc...Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline,non-steroidal anti-inflammatory drugs,statins as well as anti-tumor necrosis agents.The clinical features of druginduced liver injury are indistinguishable from idiopathic autoimmune hepatitis(AIH)as both may have positive AIH-related autoantibodies,elevated immunoglobulin G,as well as similar histopathological findings.In patients who show no clinical improvement,or there is progressive liver injury despite cessation of the suspected drug,a liver biopsy should be considered,whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH.Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury.A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper.In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature.Early identification and treatment often lead to a favorable outcome in DIAIH.展开更多
Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the...Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.展开更多
AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B...AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P= 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P= 0.01) and in controls (16% vs 34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P= 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.展开更多
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
As a chronic inflammatory disease of the liver,the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated,with prognosis and diagnosis remaining unsatisfied.Currently the only viable treatmen...As a chronic inflammatory disease of the liver,the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated,with prognosis and diagnosis remaining unsatisfied.Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation.It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure.The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice,which closely mimics the pathogenesis mechanisms and pathological changes of patients,and is regarded as the best experimental model for AIH research so far.In this paper we eluci-dated the pathogenic mechanisms of AIH and the evolution of relative animal models.We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels.Finally,we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development.展开更多
Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence ...Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence of circulating autoantibodies,as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years,a couple of new insights into the genetic aspects,clinical course and treatment of AIH have been reported,which will be the focus of this review. In particular,we concentrate on genome-wide microsatellite analysis,a novel mouse model of AIH,the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH,and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.展开更多
The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune respon...The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora(dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens(molecular mimicry). Activated gutderived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.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 ...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 naive 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-γ）,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-γ 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
AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical par...AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.展开更多
文摘Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pathogenesis of AIH.Immunosuppressive therapy is the mainstay of treatment;however,10%–25%of patients with AIH may not respond to primary therapy.Those patients are often salvaged with second-and third-line immunosuppressive therapy.Workup for other concomitant diseases should be done for patients who fail to respond to primary immunosuppressive therapy.Concurrent metabolic dysfunction-asso-ciated steatotic liver disease,alcohol-related liver disease,overlap syndrome(AIH with primary biliary cholangitis or sclerosing cholangitis),chronic hepatitis B virus,hepatitis C virus,and human immunodeficiency virus infection should be ruled out in such cases.Targeting the concomitant etiology may lead to resolution of the clinical symptoms and induce biochemical and histological remission.Isolated AIH without other etiologies for liver injury should be managed with a higher dose of steroids,azathioprine,or other immunosuppressive agents.Second-and third-line immunosuppressive agents include mycophenolate mofetil,cyclosporine,tacrolimus,infliximab,and rituximab.Patients with AIH may present with acute severe AIH(AS-AIH)and AIH-related acute on chronic liver failure,and they often require liver transplantation.The terms refractory or difficult-to-treat AIH have been used interchangeably and have no distinct definition.Difficult-to-treat AIH includes patients with intolerable side effects,fulminant disease(AIH with acute on chronic liver failure and AS-AIH),AIH in pregnancy,and HIV infection.Patients who fail to respond to standard first-line immunosuppressive therapy should be classified as refractory AIH.This review addresses the issues in the management of difficult-to-treat AIH with recent advances in pharmacological management.
文摘BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recently been explored for these difficult cases.AIM To assess the efficacy and safety of biologics in AIH,focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission.METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH.The primary focus was on serological improvement and histological remission.The secondary focus was on assessing therapy safety and additional outcomes.A standardized search command was applied to MEDLINE,EMBASE,and Cochrane Library databases to identify relevant studies.Inclusion criteria encompassed adult AIH patients treated with biologics.Data were analyzed based on demographics,prior treatments,and therapy-related outcomes.A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence.RESULTS A total of 352 studies were reviewed,with 30 selected for detailed analysis.Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies.Rituximab demonstrated high efficacy,with 41 out of 45 patients showing significant improvement across six studies.Basiliximab was assessed in a single study,where the sole patient treated experienced a beneficial outcome.Additionally,a notable number of AIH cases were induced by anti-tumor necrosis factor(TNF)medications,including 16 cases associated with infliximab and four cases with adalimumab.All these cases showed improvement upon withdrawal of the biologic agent.CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH,demonstrating significant improvements in clinical outcomes and liver function.However,the variability in patient responses to different therapies highlights the need for personalized treatment strategies.The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition.These findings support the incorporation of biologic agents into AIH treatment protocols,particularly for patients who do not respond to conventional therapies.
基金supported by a grant from the Key Project from Beijing Municipal Science and Technology Commission(D121100003912003).
文摘To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosuppressive therapy,utilizing corticosteroids and azathioprine(Imuran),which result in clinical and histological im-provement among 60%AIH patients[1,2].The diagnosis of AIH requires a combination of clinical,bio-chemical,and histological findings.The first diagnostic system was established in 1993[3],revised in 1999[4],and then a simplified criterion was proposed[5].Liver histology plays an important role in the scoring systems of AIH diagnosis and is essential to make an accurate diagnosis.Due to the lack of obvious symptoms in the early stage,about 30%patients have already progressed to cirrho-sis by the time of diagnosis[6].
文摘BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.
文摘In this article,we comment on the article by Peta et al.This study evaluates the diagnostic performance of FibroTest-Actitest,transient elastography,and the fibrosis-4 index against a histological reference.Using the Obuchowski measure,the authors demonstrate that FibroTest and vibration-controlled transient elastography outperform the fibrosis-4 index in detecting fibrosis.Additionally,Actitest offers superior estimation of inflammatory activity compared to conventional biomarkers.Assessing liver fibrosis is crucial for managing autoimmune hepatitis(AIH),yet reliance on invasive liver biopsy remains higher than in other liver diseases.This is partly due to more complex diagnostic criteria for AIH,the lack of standardized scoring for non-invasive testing,and the presence of inflammation,which can lead to falsely elevated results with non-invasive tests.A Bayesian latent class model further supports the reliability of these non-invasive tests,highlighting their potential to complement biopsy,particularly for longterm disease monitoring.These findings underscore the importance of noninvasive diagnostics in optimizing AIH management.
文摘Refractory autoimmune hepatitis(AIH)is defined as intolerance of or unresponsiveness to standard immunosuppression and occurs in 10%-20%of children with AIH.Lack of response or slower than expected response to induction of remission with steroids,despite good compliance,might be the first clue to refractory AIH.Refractoriness to treatment is associated with an 11.7 times higher risk for liver transplantation or death due to liver disease.The first and foremost consideration for the management is to assess compliance with treatment.It is then important to re-evaluate the diagnosis,assess alternative aetiologies which can mimic the clinical,serological,and histological features of AIH,and address the presence of extra-hepatic co-morbidities.It is important to consider the specific clinical situations,previous therapy,and prior adverse effects before deciding on the most appropriate treatment regimen in refractory AIH.Consideration also should be given to compliance with previous therapy,need for drug level monitoring,growth potential,available formulations,route of administration of medication,and children’s and families’preferences before deciding on the therapy.Treatment should be decided and monitored only in specialized hepatology centers.
基金Supported by Xinjiang“Tianshan Talents”Medical and Health High-Level Talent Training Program-Young and Middle-Aged Backbone Medical Talents.
文摘BACKGROUND Hepatitis D virus-hepatitis B virus(HDV-HBV)co-infection accelerates liver disease progression and increases the risk of hepatocellular carcinoma,but the immunopathogenic mechanism of its combination with autoimmune hepatitis(AIH)has not been clarified.This study reveals for the first time that HDV may induce AIH through abnormalities in immunoregulation in two specific cases.This is the first report of HDV-HBV co-infected patients who did not receive interferon therapy and achieved serological conversion and histological remission by combining antiviral(entecavir)with immunosuppression(prednisone+azathioprine)therapy,providing new evidence of the mechanism of this complex disease.CASE SUMMARY A 40-year-old female developed malaise and jaundice with an alanine aminotransferase/aspartate aminotransferase>20 upper limit of normal(ULN),total bilirubin:97.20μmol/L,immunoglobulin G(IgG)47.1 g/L(>3×ULN),HDV RNA 1.6×10^(7)copies/mL and liver biopsy showed G3S4.Tenofovir alafenamide combined with prednisone and azathioprine was administered,and three months later the Child-Turcotte-Pugh class C was reduced to class B and IgG decreased to 13.62 g/L.Another 58-year-old male complained of pain in the liver area,antinuclear antibody was 1:320,IgG 22.6 g/L(>1.3×ULN),and liver biopsy showed G2S3.Entecavir was administered in combination with prednisone and azathioprine,and after 3 months,liver function returned to normal,and IgG reduced to 14.22 g/L.CONCLUSION Patients with HDV-HBV co-infection combined with AIH can achieve clinical remission following combination therapy,and the study of immunomodulatory mechanisms should be emphasized.
文摘BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.
文摘BACKGROUND Autoimmune hepatitis(AIH)is characterized by inflammation,hepatocyte necrosis,autoantibodies,and elevated serum globulin levels.It can present at any age,with peaks reported at 30 years and after 60 years.No national studies have evaluated the impact of age at diagnosis on AIH presentation and outcomes.AIM To compare the presentation and progression of AIH in patients diagnosed before and after the age of 60 years.METHODS This cross-sectional analytical study included biopsy-confirmed AIH patients with at least one year of follow-up at Hospital Clínico Universidad de Chile,Santiago,Chile.Demographic,clinical,laboratory,and treatment response variables were analyzed.Group comparisons(diagnosis before or after 60 years)were performed using theχ2 test for qualitative variables and the Mann-Whitney test for quantitative variables(significance P<0.05).RESULTS Ninety-seven AIH patients were included;85%were female,with a median age of 53 years(range 18-83 years).Forty-one percent were diagnosed after the age of 60.Younger patients exhibited more jaundice at diagnosis(75%vs 44%,P=0.02)and higher aminotransferases levels(median alanine aminotransferase 998 IU/mL vs 334 IU/mL,P=0.0002).In contrast,at diagnosis,ascites was more prevalent in patients over 60(13%vs 2%,P=0.028),and advanced fibrosis(F3-F4)was more frequent in this group(68%vs 41%,P=0.020).Biochemical response at six months was similar between groups,despite lower corticosteroid doses being administered to patients over 60 years.CONCLUSION AIH in patients over 60 presented with less jaundice,lower aminotransferases levels,greater fibrosis,and more ascites.Biochemical response was similar independently of age and despite lower prednisone doses administered in patients over 60 years.
基金University-Level College Student Innovation and Entrepreneurship Training Program of Qiqihar Medical UniversityExploring the Mechanism of Ganjiang Huangqin Huanglian Renshen Decoction on AIH Mice Based on Network Pharmacology and In Vivo Experiments(Project No.:X202311230039)。
文摘Objective:To explore the molecular mechanism and action pathways of Wumei Pill in the treatment of autoimmune hepatitis(AIH)using network pharmacology and molecular docking methods.Methods:The active components and targets of Wumei Pill,as well as AIH-related disease targets,were screened through the TCMSP,GeneCards,OMIM,and Disgenet databases.Cytoscape 3.9.1 was used to construct a series of topological networks,followed by Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis and Gene Ontology(GO)enrichment analysis.Molecular docking and visualization were performed using AutoDockTools 1.5.7 and PyMOL 2.4.0.Results:A total of 124 active components of Wumei Pill,877 drug targets,1130 disease targets,and 64 overlapping targets were obtained.GO enrichment analysis yielded 82 biological processes,4 cellular components,and 19 molecular functions.KEGG pathway enrichment analysis identified 21 signaling pathways.Conclusion:Wumei Pill can act on targets such as Tumor Necrosis Factor(TNF),Caspase 3(CASP3),C-X-C Motif Chemokine Ligand 8(CXCL8),Nuclear Factor Kappa B Subunit 1(NFKB1),and Transforming Growth Factor Beta 1(TGFB1)through active components including girinimbine and(R)-tetrahydroberberine.It further regulates inflammation and apoptosis-related pathways such as tumorrelated signaling pathways and Th17 cell differentiation pathway to treat AIH.This study provides a theoretical basis for in-depth research on the mechanism of Wumei Pill in the treatment of AIH and the development of therapeutic drugs.
文摘Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels.Liver transplantation may be required for patients with acute liver failure,decompensated cirrhosis,and hepatocellular carcinoma.Recurrence is defined as development of the same disease in the allograft following liver transplantation.Autoimmune hepatitis recurs in 36%-68%of the recipients 5 years after liver transplantation.De novo autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis.Diagnostic work up for recurrent and de novo autoimmune hepatitis is similar to the diagnosis of the original disease,and it is usually difficult.Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and de novo autoimmune hepatitis.Early diagnosis and treatment are vital for patient prognosis because de novo autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
文摘Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline,non-steroidal anti-inflammatory drugs,statins as well as anti-tumor necrosis agents.The clinical features of druginduced liver injury are indistinguishable from idiopathic autoimmune hepatitis(AIH)as both may have positive AIH-related autoantibodies,elevated immunoglobulin G,as well as similar histopathological findings.In patients who show no clinical improvement,or there is progressive liver injury despite cessation of the suspected drug,a liver biopsy should be considered,whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH.Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury.A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper.In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature.Early identification and treatment often lead to a favorable outcome in DIAIH.
基金supported by a grant from the National Natural Science Foundation of China(81270544)
文摘Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.
文摘AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P= 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P= 0.01) and in controls (16% vs 34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P= 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.
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.
基金Supported by Program for Excellent Talents of Anhui Province,No.2006JQ1196
文摘As a chronic inflammatory disease of the liver,the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated,with prognosis and diagnosis remaining unsatisfied.Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation.It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure.The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice,which closely mimics the pathogenesis mechanisms and pathological changes of patients,and is regarded as the best experimental model for AIH research so far.In this paper we eluci-dated the pathogenic mechanisms of AIH and the evolution of relative animal models.We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels.Finally,we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development.
文摘Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence of circulating autoantibodies,as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years,a couple of new insights into the genetic aspects,clinical course and treatment of AIH have been reported,which will be the focus of this review. In particular,we concentrate on genome-wide microsatellite analysis,a novel mouse model of AIH,the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH,and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.
文摘The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora(dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens(molecular mimicry). Activated gutderived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.
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 naive 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-γ）,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-γ producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.
基金Supported by funding from Rigshospitalet,The Laerdal Foundation for Acute Medicine,Savvaerksejer Jeppe Juhl and wife Ovita Juhls Foundation,The Novo Nordisk Foundation,The AP-Mφller Foundation,and an unrestricted grant from Astellas Inc
文摘AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.
