Publications by authors named "Albert J Czaja"

147 Publications

Review article: targeting the B cell activation system in autoimmune hepatitis.

Authors:
Albert J Czaja

Aliment Pharmacol Ther 2021 10;54(7):902-922

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Background: The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis.

Aims: To describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitis METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.

Results: The B cell activating factor is crucial for the maturation and survival of B cells, and it can co-stimulate T cell activation, proliferation, and survival. It can also modulate the immune response by inducing interleukin 10 production by regulatory B cells. A proliferation-inducing ligand modulates and diversifies the antibody response by inducing class-switch recombination in B cells. It can also increase the proliferation, survival, and antigen activation of T cells. These immune stimulatory actions can be modulated by inducing proliferation of regulatory T cells. The B cell activation system has been implicated in diverse autoimmune diseases, and therapeutic blockade is a management strategy now being evaluated in autoimmune hepatitis.

Conclusions: The B cell activation system has profound effects on B and T cell function in autoimmune diseases. Blockade therapy is being actively evaluated in autoimmune hepatitis. Clarification of the critical pathogenic components of the B cell activation system will improve the targeting, efficacy, and safety of blockade therapy in this disease.
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http://dx.doi.org/10.1111/apt.16574DOI Listing
October 2021

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

Authors:
Albert J Czaja

World J Gastroenterol 2021 Jul;27(25):3705-3733

Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States.

Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The 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 implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their 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.
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http://dx.doi.org/10.3748/wjg.v27.i25.3705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291028PMC
July 2021

Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis.

Authors:
Albert J Czaja

Dig Dis Sci 2021 Apr 9. Epub 2021 Apr 9.

Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.

Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8 T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4 and CD8 T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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http://dx.doi.org/10.1007/s10620-021-06968-6DOI Listing
April 2021

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis.

Authors:
Albert J Czaja

Dig Dis Sci 2021 08 24;66(8):2493-2512. Epub 2020 Aug 24.

Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.

Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8 T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.
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http://dx.doi.org/10.1007/s10620-020-06562-2DOI Listing
August 2021

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis.

Authors:
Albert J Czaja

Aliment Pharmacol Ther 2020 06 3;51(12):1286-1304. Epub 2020 May 3.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Background: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.

Aims: To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.

Methods: English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.

Results: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.

Conclusions: The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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http://dx.doi.org/10.1111/apt.15743DOI Listing
June 2020

Autoimmune Hepatitis: Surviving Crises of Doubt and Elimination.

Authors:
Albert J Czaja

Clin Liver Dis (Hoboken) 2020 Feb 2;15(Suppl 1):S72-S81. Epub 2020 Mar 2.

Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science Rochester MN.

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http://dx.doi.org/10.1002/cld.917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050953PMC
February 2020

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

Authors:
Albert J Czaja

World J Gastroenterol 2019 Dec;25(45):6579-6606

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States.

Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The 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 impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic 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 bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions 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 outcome. In 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.
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http://dx.doi.org/10.3748/wjg.v25.i45.6579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906207PMC
December 2019

Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis.

Authors:
Albert J Czaja

Autoimmunity 2019 06 12;52(4):144-160. Epub 2019 Jul 12.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science , Rochester , MN , USA.

Key inhibitory proteins can blunt immune responses to self-antigens, and deficiencies in this repertoire may promote autoimmunity. The goals of this review are to describe the key immune inhibitory proteins, indicate their possible impact on the development of autoimmune disease, especially autoimmune hepatitis, and encourage studies to clarify their pathogenic role and candidacy as therapeutic targets. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Cytotoxic T lymphocyte antigen-4 impairs ligation of CD28 to B7 ligands on antigen presenting cells and inhibits the adaptive immune response by increasing anti-inflammatory cytokines, generating regulatory T cells, and reducing T cell activation and proliferation. Programed cell death antigen-1 inhibits T cell selection, activation, and proliferation by binding with two ligands at different phases and locations of the immune response. A soluble alternatively spliced variant of this protein can dampen the inhibitory signal. Autoimmune hepatitis has been associated with polymorphisms of the cytotoxic T lymphocyte antigen-4 gene, reduced hepatic expression of a ligand of programed cell death antigen-1, an interfering soluble variant of this key inhibitory protein, and antibodies against it. Findings have been associated with laboratory indices of liver injury and suboptimal treatment response. Abatacept, belatacept, CD28 blockade, and induction of T cell exhaustion are management considerations that require scrutiny. In conclusion, deficiencies in key immune inhibitory proteins may promote the occurrence of autoimmune diseases, such as autoimmune hepatitis, and emerging interventions may overcome these deficiencies. Investigations should define the nature, impact and management of these inhibitory disturbances in autoimmune hepatitis.
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http://dx.doi.org/10.1080/08916934.2019.1641200DOI Listing
June 2019

Letter: high ferritin to haemoglobin ratio is related to early mortality in patients with alcoholic hepatitis - author's reply.

Authors:
Albert J Czaja

Aliment Pharmacol Ther 2019 06;49(11):1457-1458

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

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http://dx.doi.org/10.1111/apt.15275DOI Listing
June 2019

Editorial: tailoring mycophenolate mofetil rescue therapy for success in autoimmune hepatitis.

Authors:
Albert J Czaja

Aliment Pharmacol Ther 2019 06;49(11):1449-1450

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN.

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http://dx.doi.org/10.1111/apt.15272DOI Listing
June 2019

Letter: vitamin D deficiency and autoimmune hepatitis - from research to treatment-authors' reply.

Aliment Pharmacol Ther 2019 04;49(8):1104-1105

Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1111/apt.15154DOI Listing
April 2019

Letter: severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis-offender or bystander? Authors' reply.

Aliment Pharmacol Ther 2019 04;49(7):959-960

Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada.

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http://dx.doi.org/10.1111/apt.15180DOI Listing
April 2019

Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications.

Authors:
Albert J Czaja

Aliment Pharmacol Ther 2019 03 13;49(6):681-701. Epub 2019 Feb 13.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome.

Aims: To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.

Results: Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists.

Conclusions: Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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http://dx.doi.org/10.1111/apt.15173DOI Listing
March 2019

Editorial: the role of vitamin D in autoimmune hepatitis-authors' reply.

Aliment Pharmacol Ther 2019 02;49(3):343-344

Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1111/apt.15091DOI Listing
February 2019

Severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis.

Aliment Pharmacol Ther 2019 01 28;49(2):173-182. Epub 2018 Nov 28.

Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada.

Background: Vitamin D deficiency has been implicated in the outcome of chronic liver disease.

Aim: To determine the frequency of severe vitamin D deficiency in autoimmune hepatitis (AIH), assess its association with treatment non-response, and evaluate the relationship between vitamin D status and liver-related mortality and need for transplantation.

Methods: Two hundred and nine patients were evaluated by liver tissue examination at presentation. Serum vitamin D levels were determined, and serum levels <25 nmol/L (10 ng/mL) were considered severely deficient. Treatment non-response was defined as non-normalised aspartate aminotransferase/alanine aminotransferase and immunoglobulin G levels during conventional immunosuppressive therapy. Univariate and multivariate analyses were performed using binary logistic regression and Cox proportional hazards model.

Results: The mean vitamin D level was 60 ± 38 nmol/L (range, 3-263 nmol/L), and 42 patients (20%) had severe vitamin D deficiency. Treatment non-response was more common in patients with severe vitamin D deficiency than in patients without (59% vs 41%, P = 0.04). Severe vitamin D deficiency was also independently associated with a higher risk of developing cirrhosis (HR 3.40; 95% CI 1.30-8.87, P = 0.01) and liver-related mortality or requirement for liver transplantation (LT; HR 5.26, 95% CI, 1.54-18.0, P = 0.008). Patients with persistent severe deficiency following vitamin D supplementation continued to have poor outcomes.

Conclusions: Severe vitamin D deficiency is associated with treatment non-response, progression to cirrhosis, and liver-related death or need for LT. Severe vitamin D deficiency is a prognostic biomarker in AIH.
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http://dx.doi.org/10.1111/apt.15029DOI Listing
January 2019

Recurrent and De Novo Autoimmune Hepatitis.

Liver Transpl 2019 01;25(1):152-166

Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada.

Clinical indications for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) are identical to those of patients with other chronic liver diseases that end in acute or semiacute liver failure, decompensated cirrhosis, or hepatocellular carcinoma. Recurrent disease after LT has been reported in 10%-50% of patients with AIH, and the frequency of detection is influenced in part by the use of protocol or clinically indicated liver biopsy. De novo AIH connotes the development of AIH in patients transplanted for liver diseases other than AIH, and it has been reported in 5%-10% of pediatric and 1%-2% of adult recipients. Recurrent disease can negatively impact on graft and patient survival, and retransplantation has been required in 8%-23%. De novo AIH is within the spectrum of graft dysfunction that includes plasma cell-rich rejection, and it can also progress to cirrhosis and graft failure. Treatment for recurrent or de novo disease is based on the conventional regimens for AIH, and corticosteroid therapy alone or combined with azathioprine is standard. Better control of disease activity prior to LT has been associated with less recurrence, and maintenance corticosteroid treatment after LT can reduce its frequency. In conclusion, recurrent AIH is far more frequent than de novo AIH. Both may have negative impacts on graft and patient survival, and early detection and treatment are key objectives. Future investigations must codify the diagnostic criteria for each graft dysfunction, seek diagnostic biomarkers, and evaluate treatments that improve outcomes without increasing the risk of pre- and post-LT infections.
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http://dx.doi.org/10.1002/lt.25375DOI Listing
January 2019

Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis.

Dig Dis Sci 2019 02 28;64(2):324-344. Epub 2018 Oct 28.

Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are to describe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote disease progression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.
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http://dx.doi.org/10.1007/s10620-018-5351-6DOI Listing
February 2019

Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management.

Authors:
Albert J Czaja

Dig Dis Sci 2018 07 18;63(7):1706-1725. Epub 2018 Apr 18.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.

Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.
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http://dx.doi.org/10.1007/s10620-018-5072-xDOI Listing
July 2018

Autoimmune hepatitis.

Nat Rev Dis Primers 2018 04 12;4:18017. Epub 2018 Apr 12.

Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.

Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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http://dx.doi.org/10.1038/nrdp.2018.17DOI Listing
April 2018

Emerging therapeutic biomarkers of autoimmune hepatitis and their impact on current and future management.

Authors:
Albert J Czaja

Expert Rev Gastroenterol Hepatol 2018 Jun 20;12(6):547-564. Epub 2018 Mar 20.

a Division of Gastroenterology and Hepatology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA.

Introduction: Autoimmune hepatitis lacks a quantifiable biomarker that is close to its pathogenic mechanisms and that accurately reflects inflammatory activity, correlates with treatment response, and ensures inactive disease before treatment withdrawal. Areas covered: Micro-ribonucleic acids, programmed death-1 protein and its ligands, macrophage migration inhibitory factor, soluble CD163, B cell activating factor, and metabolite patterns in blood were considered the leading candidates as therapeutic biomarkers after search of PubMed from August 1981 to August 2017 using the search words 'biomarkers of autoimmune hepatitis'. Expert commentary: Each of the candidate biomarkers is close to the putative pathogenic mechanisms of autoimmune hepatitis, and each has attributes that support its potential role as a surrogate marker of inflammatory activity that can be monitored during treatment. Future studies must demonstrate the superiority of each biomarker to conventional indices of inflammatory activity and validate their correlation with treatment response and outcome. A reliable therapeutic biomarker would facilitate the individualization of current management algorithms, ensure that pathogenic mechanisms were disrupted or eliminated prior to treatment withdrawal, and reduce the frequency of relapse or unnecessary protracted therapy. The biomarker might also prove to be a target of next-generation therapies.
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http://dx.doi.org/10.1080/17474124.2018.1453356DOI Listing
June 2018

Epigenetic changes and their implications in autoimmune hepatitis.

Authors:
Albert J Czaja

Eur J Clin Invest 2018 Apr 18;48(4). Epub 2018 Feb 18.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Background: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention.

Materials And Methods: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150.

Results: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain.

Conclusions: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.
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http://dx.doi.org/10.1111/eci.12899DOI Listing
April 2018

Global Disparities and Their Implications in the Occurrence and Outcome of Autoimmune Hepatitis.

Authors:
Albert J Czaja

Dig Dis Sci 2017 09 14;62(9):2277-2292. Epub 2017 Jul 14.

Division of Gastroenterology and Hepatology, Professor Emeritus of Medicine, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.

Autoimmune hepatitis has a variable occurrence, clinical phenotype, and outcome, and the factors contributing to this variability are uncertain. The goals of this review are to examine the global disparities in the occurrence and outcome of autoimmune hepatitis, suggest bases for these disparities, and encourage investigations that extend beyond single-center experiences. Disparities in the incidence and prevalence of autoimmune hepatitis in different age groups, genders, ethnicities, and geographical regions suggest that factors other than genetic predisposition are involved. Age- and gender-related antigen exposures from the external (infections, toxins, and medications) and internal (intestinal microbiome) environment may affect the incidence of the disease, and the timeliness and nature of treatment may influence its prevalence. The increasing incidence of autoimmune hepatitis in Spain, Denmark, and the Netherlands suggests that a new etiological trigger has been introduced or that the susceptible population has changed. Variations in mortality between Western and Asian-Pacific countries may result from differences in disease detection or management, and variations in gender predilection, peak age of onset, frequency of concurrent immune diseases, and serological profile may reflect gender-biased and age-related antigen exposures and genetic predispositions. Global collaborations, population-based epidemiological studies that identify case clustering, and controlled interview-based surveys are mechanisms by which to understand these disparities and improve management. In conclusion, autoimmune hepatitis has a rising incidence in some countries and variable occurrence, phenotype, and outcome between countries and subgroups within countries. These disparities suggest that unrecognized population-based environmental, infectious, or socioeconomic factors are affecting its character.
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http://dx.doi.org/10.1007/s10620-017-4675-yDOI Listing
September 2017

Autoimmune Hepatitis Overlap Syndromes and Liver Pathology.

Gastroenterol Clin North Am 2017 06;46(2):345-364

Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA.

Autoimmune hepatitis (AIH) may have an atypical serum alkaline phosphatase elevation, antimitochondrial antibodies, histologic features of bile duct injury/loss, or cholangiographic findings of focal biliary strictures and dilations. These manifestations characterize the overlap syndromes. Patients can be classified as having AIH with features of primary biliary cholangitis, primary sclerosing cholangitis, or a cholestatic syndrome. The gold standard of diagnosis is clinical judgment. Histologic evaluation is a major diagnostic component. Treatment is based on algorithms; outcomes vary depending on the predominant disease component. Combination therapy has been the principal recommendation.
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http://dx.doi.org/10.1016/j.gtc.2017.01.008DOI Listing
June 2017

Evolving paradigm of treatment for autoimmune hepatitis.

Authors:
Albert J Czaja

Expert Rev Clin Immunol 2017 08 21;13(8):781-798. Epub 2017 Apr 21.

a Professor Emeritus of Medicine , Mayo Clinic College of Medicine , Rochester , MN , USA.

Introduction: Current medications for autoimmune hepatitis have broad anti-inflammatory and immunosuppressive actions, and their effects are short-lived and inconsistent. The goals of this review were to describe the actions and shortcomings of these medications, indicate the key pathogenic mechanisms that might be targeted by site-directed interventions, and present the pivotal studies supporting development of these alternative agents. Areas covered: Abstracts cited in PubMed from April 1964 to February 2017 were identified using the search words 'treatment of autoimmune hepatitis'. A secondary bibliography was developed from the references cited in selected articles, and additional searches were performed to expand the concepts developed in these articles. The number of abstracts reviewed exceeded 1000, and the number of full-length articles reviewed exceeded 100. Expert commentary: Molecular, cellular, and pharmacological interventions that target key pathogenic pathways promise to change the current paradigm of treatment for autoimmune hepatitis. Interventions affecting lymphocyte activation, lymphocyte differentiation, effector cell migration, hepatocyte apoptosis, oxidative-nitrosative stress, fibrogenesis, and intestinal dysbiosis promise to emerge as supplemental or replacement therapies. The intestinal microbiome constitutes the next investigational frontier that may influence future management strategies. Unwanted and unexpected consequences of manipulating these homeostatic pathways constitute the major unmeasured risks of these evolving regimens.
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http://dx.doi.org/10.1080/1744666X.2017.1319764DOI Listing
August 2017

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

World J Gastroenterol 2017 Feb;23(5):859-868

Jin Wang, Neera Malik, Meng Yin, Richard L Ehman, Sudhakar K Venkatesh, Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, United States.

Aim: 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 radiologists evaluated 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/cirrhosis.

Results: 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 ( = 0.88 -0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed (3.7 kPa 3.84 kPa) 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 0.53-0.80, < 0.01), and cirrhosis (0.98 0.58-0.80, < 0.01) and better than conventional MRI for diagnosis of cirrhosis (0.98 0.78, = 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.
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http://dx.doi.org/10.3748/wjg.v23.i5.859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296202PMC
February 2017

Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis.

Authors:
Albert J Czaja

World J Gastroenterol 2016 Nov;22(42):9257-9278

Albert J Czaja, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States.

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 gut-derived 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.
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http://dx.doi.org/10.3748/wjg.v22.i42.9257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107691PMC
November 2016

Targeting Hepatic Fibrosis in Autoimmune Hepatitis.

Dig Dis Sci 2016 11 19;61(11):3118-3139. Epub 2016 Jul 19.

Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.

Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.
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http://dx.doi.org/10.1007/s10620-016-4254-7DOI Listing
November 2016

Nature and Implications of Oxidative and Nitrosative Stresses in Autoimmune Hepatitis.

Authors:
Albert J Czaja

Dig Dis Sci 2016 10 13;61(10):2784-2803. Epub 2016 Jul 13.

Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.

Oxidative and nitrosative stresses can damage cellular membranes, disrupt mitochondrial function, alter gene expression, promote the apoptosis and necrosis of hepatocytes, and increase fibrosis in diverse acute and chronic liver diseases, including autoimmune hepatitis. The objectives of this review are to describe the mechanisms of oxidative and nitrosative stresses in inflammatory liver disease, indicate the pathogenic implications of these stresses in autoimmune hepatitis, and suggest investigational opportunities to develop interventions that counter them. The principal antioxidant defenses, including glutathione production, the activities of antioxidant enzymes, and the release of the nuclear factor erythroid 2-related factor 2, may be inadequate or suppressed by transforming growth factor beta. The generation of reactive oxygen species can intensify nitrosative stress, and this stress may not be adequately modulated by the thioredoxin-thioredoxin reductase system and induce post-translational modifications of proteins that further disrupt hepatocyte function. The unfolded protein response and autophagy may be unable to restore redox stability, meet metabolic demands, and maintain hepatocyte survival. Emerging interventions with highly selective site- and organelle-specific actions may improve outcomes, and they include inhibitors of nicotinamide adenine dinucleotide phosphate oxidase, nitric oxide synthase, and transforming growth factor beta. Pharmacological manipulation of nuclear transcription factors may favor expression of antioxidant genes, and stimulation of chaperone proteins within the endoplasmic reticulum and modulation of autophagy may prevent hepatic fibrosis and enhance cell survival. These interventions constitute investigational opportunities to improve the management of autoimmune hepatitis.
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http://dx.doi.org/10.1007/s10620-016-4247-6DOI Listing
October 2016
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