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Difficult treatment decisions in autoimmune hepatitis

World journal of Gastroenterology 2010年第8期16卷 934-947页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine

Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.

关键词： Autoimmune hepatitis Fulminant hepatitis Salvage therapy Treatment end points

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Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions

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World journal of Gastroenterology 2019年第45期25卷 6579-6606页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science

BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis,but they have not fully explained susceptibility,triggering events,and maintenance or escalation of the ***,they have not identified a critical defect that can be *** goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis,indicate investigational opportunities to validate their contribution,and suggest interventions that might evolve to modify their *** abstracts were identified in PubMed by multiple search *** length articles were selected for review,and secondary and tertiary bibliographies were *** and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory *** dysfunction,possibly related to deficient production of programmed cell death protein-1,can allow autoreactive T cells to escape deletion,and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender *** factors may trigger the disease or induce epigenetic changes in gene *** mimicry,epitope spread,bystander activation,neo-antigen production,lymphocytic polyspecificity,and disturbances in immune inhibitory mechanisms may maintain or escalate the *** that modify epigenetic effects on gene expression,alter intestinal dysbiosis,eliminate deleterious environmental factors,and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk,individualize management,and improve *** conclusion,diverse pathogenic mechanisms have been implicated in autoimmune hepatitis,and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.

关键词： Autoimmune hepatitis Pathogenesis Epigenetics Molecular mimicry Epitope spread Intestinal microbiome

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Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

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World journal of Gastroenterology 2016年第42期22卷 9257-9278页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine

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.

关键词：肠的 microbiome Inflammasomes 自体免疫的肝炎 Dysbiosis 像使用费的受体

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Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

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World journal of Gastroenterology 2021年第25期27卷 3705-3733页

作者： albert j czaja Department of Medicine Mayo Clinic College of Medicine and ScienceRochesterMN 55905United States

Mucosal-associated invariant T(MAIT)cells have been described in liver and nonliver diseases,and they have been ascribed antimicrobial,immune regulatory,protective,and pathogenic *** goals of this review are to describe their biological properties,indicate their involvement in chronic liver disease,and encourage investigations that clarify their actions and therapeutic *** abstracts were identified in PubMed by multiple search terms,and bibliographies were *** cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory *** pro-inflammatory,anti-inflammatory,and immune regulatory cytokines are released;infected cells are eliminated;and memory cells *** MAIT cells are hyper-activated,immune exhausted,dysfunctional,and depleted in chronic liver *** phenotype lacks disease-specificity,and it does not predict the biological *** cells have presumed protective actions in chronic viral hepatitis,alcoholic hepatitis,non-alcoholic fatty liver disease,primary sclerosing cholangitis,and decompensated *** have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary *** factors in the hepatic microenvironment(cytokines,bile acids,gut-derived bacterial antigens,and metabolic by-products)may modulate their response in individual *** manipulations of function are warranted to establish an association with disease severity and *** conclusion,MAIT cells constitute a disease-nonspecific,immune response to chronic liver inflammation and *** pathological role has been deduced from their deficiencies during active liver disease,and future investigations must clarify this role,link it to outcome,and explore therapeutic interventions.

关键词： Innate-like lymphocytes Antimicrobial Immune regulatory Pathogenic Mucosal-associated invariant T cell

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Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment

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World journal of Gastroenterology 2009年第19期15卷 2314-2328页

作者： albert j czaja Yusuf Bayraktar Division of Gastroenterology and Hepatology Mayo Clinic College of MedicineRochesterMinnesotaUnited States and the Department of GastroenterologyHacettepe University School of MedicineAnkara 06100Turkey

Non-classical manifestations of autoimmune hepatitis can delay diagnosis and *** aims were to describe the clinical phenotypes that can confound the diagnosis,detail scoring systems that can ensure their recognition,and outline advances in treatment that can improve their *** source and review articles in English were selected through Medline from 1970-2008 and assimilated into personal libraries spanning 32 *** severe or asymptomatic presentations and atypical histological findings,including centrilobular zone 3 necrosis and concurrent bile duct changes,are compatible with the *** abnormalities may be present in children and adults with the disease,and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic *** patients frequently become symptomatic;mild disease can progress;and there are no conf ident indices that justify withholding *** diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing *** liver tests and tissue constitute the optimal end point of treatment,and the f irst relapse is an indication for long-term azathioprine ***,tacrolimus and mycophenolate mofetil are promising salvage therapies,and budesonide with azathioprine may be a superior frontline *** conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly,diagnosed accurately,and treated effectively.

关键词：自身免疫性肝炎经典型延迟诊断抢救治疗正常肝组织诊治评分系统胆管畸形

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Hepatic inflammation and progressive liver fibrosis in chronic liver disease

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World journal of Gastroenterology 2014年第10期20卷 2515-2532页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester MN 55905 United States

Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this *** fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory ***,however,are commonly incomplete and inconsistently *** fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive *** C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within *** can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen ***-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental ***-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.

关键词： Inflammation Fibrosis Cirrhosis Treatment Anti-oxi

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Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis

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World journal of Gastroenterology 2017年第5期23卷 859-868页

作者： jin Wang Neera Malik Meng Yin Thomas C Smyrk albert j czaja Richard L Ehman Sudhakar K Venkatesh Department of Radiology Mayo Clinic College of MedicineMayo Clinic Department of Radiology the Third Affiliated HospitalSun Yat-Sen University Laboratory Medicine and Pathology Mayo Clinic College of MedicineMayo Clinic Department of Gastroenterology and Hepatology Mayo Clinic College of MedicineMayo Clinic

To assess the value of magnetic resonance elastography(MRE) in detecting advanced fibrosis/cirrhosis in autoimmune hepatitis(AIH).METHODS In this retrospective study, 36 patients(19 treated and 17 untreated) with histologically confirmed AIH and liver biopsy performed within 3 mo of MRE were identified at a tertiary care referral center. Liver stiffness(LS) with MRE was calculated by a radiologist, and inflammation grade and fibrosis stage in liver biopsy was assessed by a pathologist in a blinded fashion. Two radiologistsevaluated morphological features of cirrhosis on conventional magnetic resonance imaging(MRI). Accuracy of MRE was compared to laboratory markers and MRI for detection of advanced fibrosis/*** Liver fibrosis stages of 0, 1, 2, 3 and 4 were present in 4, 6, 7, 6 and 13 patients respectively. There were no significant differences in distribution of fibrosis stage and inflammation grade between treated and untreated patient groups. LS with MRE demonstrated stronger correlation with liver fibrosis stage in comparison to laboratory markers for chronic liver disease(r = 0.88 vs-0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed(3.7 k Pa vs 3.84 k Pa) but was not statistically significant. MRE had an accuracy/sensitivity/specificity/positive predictive value/negative predictive value of 0.97/90%/100%/100%/90% and 0.98/92.3%/96%/92.3%/96% for detection of advanced fibrosis and cirrhosis, respectively. The performance of MRE was significantly better than laboratory tests for detection of advanced fibrosis(0.97 vs 0.53-0.80, P < 0.01), and cirrhosis(0.98 vs 0.58-0.80, P < 0.01) and better than conventional MRI for diagnosis of cirrhosis(0.98 vs 0.78, P = 0.002).CONCLUSION MRE is a promising modality for detection of advanced fibrosis and cirrhosis in patients with AIH with superior diagnostic accuracy compared to laboratory assessment and MRI.

关键词：自体免疫的肝炎先进纤维变性磁性的回声 elastography 肝僵硬肝硬化

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Genetic distinctions between autoimmune hepatitis in Italy and North America

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World journal of Gastroenterology 2005年第12期11卷 1862-1866页

作者： Paolo Muratori albert j.czaja Luigi Muratori Georgios Pappas Silvana Maccariello Fabio Cassani Alessandro Granito Rodolfo Ferrari Vilma Mantovani Marco Lenzi Francesco B.Bianchi Department of Internal Medicine Division of Gastroenterology and Hepatology Laboratorio Centralizzato Settore Genetica

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 ***: Human leukocyte antigens (HLA) B8, C7, DR3,DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate ***: 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% vs48%, P = 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs43%,P= 0.01) and in controls (16% vs34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs35%, P= 0.01).CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for ATH 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.

关键词：遗传因素自身免疫肝炎意大利北美洲

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Evaluating Methods of Visual Assistance for Workers to Improve Quality and Usability in Individualized Kitchen Cabinet Assembly

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journal of Computer and Communications 2024年第2期12卷 156-172页

作者： albert Eff Michael S. j. Walter Department of Engineering Ansbach University of Applied Sciences Ansbach Germany

In times of digitalisation, visual assistance systems in assembly are increasingly important. The design of these assembly systems needs to be highly complex to meet the requirements. Due to the increasing number of variants in production processes, as well as shorter innovation and product life cycles, assistance systems should improve quality and reduce complexity of assembly processes. However, many large kitchen manufacturers still assemble kitchen cabinets manually, due to the high variety of components, such as rails and fittings. This paper focuses on the analysis and evaluation of virtual assistance systems to improve quality and usability in individualised kitchen cabinet assembly processes at a large German manufacturer. A solution is identified and detailed.

关键词： Digitalisation Assembly Process Visual Assistance Usability Human-Centred Assembly Design

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Network analyses:Inhibition of androgen receptor signaling reduces inflammation in the lung through AR-MAF-IL6 signaling axes

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Genes & Diseases 2024年第3期11卷 140-143页

作者： albert R.Wang Andrew M.Baschnagel Zijian Ni Sean R.Brennan Hypatia K.Newton Darya Buehler Christina Kendziorski Randall j.Kimple Gopal lyer Department of Human Oncology University of Wisconsin School of Medicine and Public HealthUniversity of WisconsinMadisonWI 53705USA Department of Biomedical Engineering University of Wisconsin-MadisonMadisonWI 53705USA University of Wisconsin Carbone Cancer Center MadisonWI 53705USA Department of Biostatistics and Medical Informatics University of Wisconsin-MadisonMadisonWI 53706USA Department of Biology Tufts UniversityMedfordMA 02155USA Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public HealthUniversity of WisconsinMadisonWI 53705USA

Androgen receptor(AR)is a major transcription factor that plays a role in inflammatory response including interleukin-6(IL6)signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied,its impact through an IL6 autocrine loop in the lung has not been wellstudied despite the organ's response to respiratory viral *** inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells.

关键词： inflammation lung respiratory

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