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Gromadzka G, Czerwińska J, Krzemińska E, Przybyłkowski A, Litwin T. Wilson's Disease-Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues. Int J Mol Sci 2024; 25:9034. [PMID: 39201720 PMCID: PMC11354778 DOI: 10.3390/ijms25169034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 09/03/2024] Open
Abstract
Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD.
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Affiliation(s)
- Grażyna Gromadzka
- Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego Street 1/3, 01-938 Warsaw, Poland
| | - Julia Czerwińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Elżbieta Krzemińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland;
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland;
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Song D, Rong Y, Zhang C, Sun Y. The Relationship between Choroidal Thickness and Liver Damage in Simple Auto-immune Hepatitis Patients. Niger J Clin Pract 2023; 26:1910-1915. [PMID: 38158360 DOI: 10.4103/njcp.njcp_435_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/11/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND There was no sufficient clinical evidence on the relationship between auto-immune hepatitis (AIH) and risk of eye illness, except 11 uveitis cases where related AIH is reported currently. AIM To determine the relationship between choroidal thickness (ChT) and liver damage in simple AIH patients without ocular symptoms after oral prednisone treatment. PATIENTS AND METHODS This prospective observational study included simple AIH patients. The patients' ChT was measured by swept-source (SS)-optical coherence tomography (OCT), and the liver damage was evaluated by alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ChT and liver functions were assessed prior to and after treatment. Then comparisons were made prior to and post treatment. The relationships between biochemical indexes of liver injury and ChT were evaluated after a mean (SD) of 24 (1.28) weeks of regular oral prednisone. RESULTS A total of 35 patients (31 females, aged 45.66 ± 11.62 years) were included. After treatment, ChT was significantly increased in all sectors (including the center sector, superior inner sector, inner nasal sector, inferior inner sector, inner temporal sector, superior outer sector, outer nasal sector, inferior outer sector, and outer temporal sector) (all P < 0.001). After treatment, both ALT (51.34 ± 44.16 vs 255.06 ± 107.84, P < 0.001) and AST (38.66 ± 27.12 vs 164.89 ± 85.58, P < 0.001) were significantly decreased. The increase of ChT in all sectors was significantly related to the decrease of ALT and AST (all P < 0.001). CONCLUSION The improvement of ChT might reflect the remission of liver damage in simple AIH patients without ocular symptoms during oral prednisone treatment.
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Affiliation(s)
- D Song
- Department of Ophthalmology, Beijing University International Hospital, No. 1 Shengmingyuan Road, Zhongguancun Life Science Park, Changping District, Beijing, China
| | - Y Rong
- Department of Liver Disease, Beijing University International Hospital, No. 1 Shengmingyuan Road, Zhongguancun Life Science Park, Changping District, Beijing, China
| | - C Zhang
- Department of Ophthalmology, Beijing University International Hospital, No. 1 Shengmingyuan Road, Zhongguancun Life Science Park, Changping District, Beijing, China
| | - Y Sun
- Department of Liver Disease-Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, No. 100 Xisihuanzhong Road, Fengtai District, Beijing, China
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
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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Affiliation(s)
- Albert J Czaja
- 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.
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Changes in Th1/Th2-related cytokine expression in the saliva of patients with recurrent aphthous stomatitis before and after prednisone treatment. Clin Oral Investig 2022; 26:1089-1093. [DOI: 10.1007/s00784-021-04349-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/18/2021] [Indexed: 12/15/2022]
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Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis. Dig Dis Sci 2021; 66:2493-2512. [PMID: 32833154 DOI: 10.1007/s10620-020-06562-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/12/2020] [Indexed: 12/11/2022]
Abstract
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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McNally BB, Carey EJ. Azathioprine Monotherapy Is Equivalent to Dual Therapy in Maintaining Remission in Autoimmune Hepatitis. Dig Dis Sci 2021; 66:1715-1719. [PMID: 32436124 DOI: 10.1007/s10620-020-06347-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 05/12/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Standard of care treatment for AIH includes prednisone monotherapy or dual therapy prednisone-azathioprine. However, many hepatologists alternatively use azathioprine monotherapy to avoid side effects of long-term corticosteroids. AIMS To determine whether azathioprine monotherapy is comparable to dual prednisone-azathioprine for maintenance of remission in AIH. METHODS A retrospective chart review of 260 individuals with AIH from a single institution was performed; 45 individuals were included. Exclusion criteria included concomitant PBC or PSC, use of alternative treatment regimen, and/or failure to reach remission. Treatment regimen received was guided by clinician standard of practice, not patients' clinical factors. Initial remission was defined as normalization of serum ALT for at least two consecutive blood draws. Data were analyzed for 5 years post-remission, recording outcome and dose of prednisone and/or azathioprine. RESULTS 83% of individuals were female, and average age was 65 years. Median dose of prednisone and azathioprine for the dual-therapy group was 5 mg and 100 mg, respectively, while median azathioprine dose for the monotherapy group was 75 mg. Considering overall outcome, 93% of all patients maintained remission. 80% of the dual-therapy group, and 95% of the azathioprine monotherapy group maintained remission. Using Chi-square analysis to compare the maintenance of remission between dual therapy and azathioprine monotherapy, a p value of 0.28 was calculated. CONCLUSIONS AASLD guidelines recommend dual prednisone-azathioprine as standard of care for maintenance of remission in AIH. Our results suggest that azathioprine monotherapy is equivalent to prednisone-azathioprine. Azathioprine monotherapy offers a significant advantage in mitigating risks of long-term corticosteroid therapy.
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Affiliation(s)
- Bridgette B McNally
- Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Ave, Glendale, AZ, 85308, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.
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Lu FB, Hu ED, Xu LM, Hu YB, Chen L, Wu JL, Li H, Chen DZ, Chen YP. Comparative efficacy and tolerability of treatments for adult autoimmune hepatitis: A systematic review and network meta-analysis. Exp Ther Med 2018; 15:4838-4850. [PMID: 29904396 PMCID: PMC5996682 DOI: 10.3892/etm.2018.6063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 12/06/2017] [Indexed: 01/30/2023] Open
Abstract
The most suitable treatment regimen for autoimmune hepatitis (AIH) in adults remains unknown and requires further investigation. The current study therefore aimed to integrate evidence to provide hierarchies of the comparative efficacies of treatments measured by clinical and biochemical remission. A Bayesian-framework network meta-analysis of randomized controlled trials (RCTs) was preformed to compare eight treatments for AIH. Eligible RCTs were identified by searching Embase, Pubmed and the Cochrane Library for publications between 1966 and April 2017. All outcomes were independently extracted from the included studies by two authors. A total of six RCTs were subsequently included in the current study. The network of comparisons on remission indicated that patients treated with prednisone (pred) experienced significantly increased rates of remission compared with those treated with azathioprine [AZA; odds ratio (OR), 0.21; 95% confidence interval (CI), 0.06-0.71] and budesonide (bude) + AZA significantly increased remission compared with placebo treatment (OR, 36.66; 95% CI, 1.40-962.49) or AZA (OR, 10.30; 95% CI, 1.50-70.70). Based on the cumulative ranking probabilities, bude + AZA (89.4) was ranked first, pred (69.1) was ranked second, pred + AZA (63.2) was ranked third and placebo (7.8) treatment was ranked last. Bude + AZA may be the most appropriate candidate for the treatment of non-cirrhotic patients. However, bude + AZA as frontline therapy for AIH requires more large-scale studies with a longer duration of follow-up histology and a focus on dose-response. Additionally, development of other prospective treatments, which may be used as alternative therapy or first line therapy, and their subsequent evaluation in clinical RCTs is required.
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Affiliation(s)
- Feng-Bin Lu
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - En-De Hu
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lan-Man Xu
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yi-Bing Hu
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Jinhua, Zhejiang 321000, P.R. China
| | - Lu Chen
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jin-Lu Wu
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Hui Li
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Da-Zhi Chen
- State Key Laboratory of Infectious Diseases, Medicine School of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Yong-Ping Chen
- Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Czaja AJ, Carpenter HA. Autoimmune Hepatitis Overlap Syndromes and Liver Pathology. Gastroenterol Clin North Am 2017; 46:345-364. [PMID: 28506369 DOI: 10.1016/j.gtc.2017.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
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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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA.
| | - Herschel A Carpenter
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA
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Affiliation(s)
- Albert J. Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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Cai X, Weng HH, Miao LY. Yinzhihuang injection for treatment of patients with autoimmune hepatitis: Clinical efficacy and impact on hepatic fibrosis indexes. Shijie Huaren Xiaohua Zazhi 2017; 25:726-731. [DOI: 10.11569/wcjd.v25.i8.726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the clinical effects of Yinzhihuang injection in the treatment of patients with autoimmune hepatitis (AIH)and its effect on indexes of hepatic fibrosis.
METHODS Seventy-four patients with AIH treated at our hospital between April 2013 and November 2015 were randomly divided into either a control group or an observation group, with 37 cases in each group. Both groups were given oral prednisone and azathioprine, and the observation group was additionally given Yinzhihuang injection. The clinical indicators, clinical curative effects and adverse reactions of the two groups were compared.
RESULTS After treatment, serum alanine aminotransferase, aspartate transaminase, glutamyl transpeptidase, total bilirubin, glyoxalase and albumin in the observation group were significantly lower than those in the control group (t = 5.056, 8.186, 7.254, 3.959, 2.928, and 2.460, respectively; P < 0.05); liver fiber indexes collagen Ⅳ, hyaluronan, procollagen Ⅲ peptide, and laminin in the observation group were significantly lower than those of the control group (t = 8.043, 12.692, 4.858, and 8.683, respectively; P < 0.05); and the ratio of CD4+ T cells/CD8+ T cells was significantly lower in the observation group than in the control group (t = 2.708, P < 0.05). The total effective rate in the observation group (89.19%) was significantly higher than that of the control group (64.86%) (χ2 = 6.186, P = 0.013). The overall incidence of adverse reactions in the observation group was significantly lower than that of the control group (5.41% vs 21.62%, χ2 = 4.163, P = 0.041).
CONCLUSION Yinzhihuang injection combined with Western medicine can significantly improve clinical efficacy and liver fiber indexes, and reduce adverse reactions in patients with AIH.
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Lin M, Pappas SC. Diabetes, Specific Hepatobiliary Diseases, and Treatment. MANAGING GASTROINTESTINAL COMPLICATIONS OF DIABETES 2017:93-105. [DOI: 10.1007/978-3-319-48662-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Montano-Loza AJ, Thandassery RB, Czaja AJ. Targeting Hepatic Fibrosis in Autoimmune Hepatitis. Dig Dis Sci 2016; 61:3118-3139. [PMID: 27435327 DOI: 10.1007/s10620-016-4254-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 07/11/2016] [Indexed: 02/06/2023]
Abstract
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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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Ragesh B Thandassery
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.
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Abstract
Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.
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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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Adiponectin as an anti-fibrotic and anti-inflammatory adipokine in the liver. CURRENT PATHOBIOLOGY REPORTS 2015; 3:243-252. [PMID: 26858914 DOI: 10.1007/s40139-015-0094-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic fibrosis is a dynamic process resulting from excessive deposition of extracellular matrix in the liver; uncontrolled progression of fibrosis can eventually lead to liver cirrhosis and/or hepatocellular carcinoma. The fibrogenic process is complex and modulated by a number of both hepatic and extra-hepatic biological factors. Growing evidence indicates that adipokines, a group of cytokines produced by adipose tissue, impart dynamic functions in liver and are involved in modulation of hepatic fibrosis. In particular, two key adipokines, adiponectin and leptin, directly regulate many biological responses closely associated with development and progression of hepatic fibrosis. Leptin acts as a pro-fibrogenic cytokine, while adiponectin possesses anti-fibrogenic and anti-inflammatory properties. Adiponectin, acting via its cognate receptors, adiponectin receptors 1 and 2, potently suppresses fibrosis and inflammation in liver via multiple mechanisms. This review summarizes recent findings concerning the role of adiponectin in fibrogenic process in liver and addresses the underlying molecular mechanisms in modulation of fibrosis.
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Potent natural products and herbal medicines for treating liver fibrosis. Chin Med 2015; 10:7. [PMID: 25897319 PMCID: PMC4403904 DOI: 10.1186/s13020-015-0036-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 04/01/2015] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a wound-healing response to chronic liver injury characterized by progressive inflammation and deposition of extracellular matrix components. The pathological condition of liver fibrosis involves secretion of extracellular matrix proteins and formation of scar tissue. The major regulators involved in hepatic fibrogenesis are the transforming growth factor (TGF)-β1/SMAD and toll-like receptor 4 (TLR4)-initiated myeloid differentiation primary response 88 gene (MyD88)/NF-ĸB cell signaling pathways. This article reviews natural products and herbal medicines that have demonstrated activity against liver fibrosis through different mechanisms of action, including anti-hepatitis B and C virus activity, anti-inflammation, inhibition of cytokine production and nuclear receptor activation, and free radical scavenging.
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Abstract
Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure.
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Gao F, Ju J, Hu MM, Yan FY, Wang XQ. Progress in pharmaceutical therapy of autoimmune liver diseases. Shijie Huaren Xiaohua Zazhi 2014; 22:4087-4093. [DOI: 10.11569/wcjd.v22.i27.4087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Autoimmune liver diseases (AILDs) include autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndrome (OS). AILDs are the new research hotspot in the field of liver diseases nowadays. The advances in research of AILDs have led to a new understanding of pharmaceutical treatment of this disease. This article reviews the progress in the pharmaceutical therapy of AILDs.
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Abstract
INTRODUCTION Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions. AREAS COVERED PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects. EXPERT OPINION Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, From the Division of Gastroenterology and Hepatology , 200 First Street S.W, Rochester, MN 55905 , USA +1 507 284 2691 ; +1 507 284 0538 ;
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Challenges in the diagnosis and management of autoimmune hepatitis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:531-9. [PMID: 24078938 DOI: 10.1155/2013/981086] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Autoimmune hepatitis has diverse clinical phenotypes and outcomes that challenge current diagnostic criteria and management algorithms. OBJECTIVES To highlight the major difficulties in diagnosis and management, describe the efforts to ease them and encourage further progress in problem solving. METHODS The MEDLINE database was reviewed for published experiences from 1984 to 2013. RESULTS Acute or acute severe (fulminant) hepatitis, asymptomatic mild disease, and histological findings of centrilobular necrosis or bile duct injury can confound diagnosis and treatment. Continuation of conventional therapy until normal liver test results and liver tissue reduces the frequency of relapse, but does not prevent its occurrence. Problematic patients can be identified using mathematical models, clinical phenotype, serological markers and the speed of improvement after treatment; however, their recognition and treatment are inconsistent. Mycophenolate mofetil can rescue patients with azathioprine intolerance but is less effective for refractory disease. Budesonide in combination with azathioprine can be used frontline, but is effective primarily in noncirrhotic, uncomplicated disease. Molecular and cellular interventions are feasible but largely unevaluated. DISCUSSION Resolution of the current challenges requires revision of diagnostic criteria, characterization of biological markers that reflect pathogenic pathways, development of dynamic indexes based on changes in disease behaviour, and introduction of new pharmacological, molecular and cellular interventions that have undergone rigorous evaluation. CONCLUSION These challenges reflect important remediable deficiencies in current management.
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Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
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Kwon HJ, Won YS, Park O, Feng D, Gao B. Opposing effects of prednisolone treatment on T/NKT cell- and hepatotoxin-mediated hepatitis in mice. Hepatology 2014; 59:1094-106. [PMID: 24115096 PMCID: PMC3943761 DOI: 10.1002/hep.26748] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 09/12/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Prednisolone is a corticosteroid that has been used to treat inflammatory liver diseases such as autoimmune hepatitis and alcoholic hepatitis. However, the results have been controversial, and how prednisolone affects liver disease progression remains unknown. In the current study we examined the effect of prednisolone treatment on several models of liver injury, including T/NKT cell hepatitis induced by concanavalin A (ConA) and α-galactosylceramide (α-GalCer), and hepatotoxin-mediated hepatitis induced by carbon tetrachloride (CCl4 ) and/or ethanol. Prednisolone administration attenuated ConA- and α-GalCer-induced hepatitis and systemic inflammatory responses. Treating mice with prednisolone also suppressed inflammatory responses in a model of hepatotoxin (CCl4 )-induced hepatitis, but surprisingly exacerbated liver injury and delayed liver repair. In addition, administration of prednisolone also enhanced acetaminophen-, ethanol-, or ethanol plus CCl4 -induced liver injury. Immunohistochemical and flow cytometric analyses demonstrated that prednisolone treatment inhibited hepatic macrophage and neutrophil infiltration in CCl4 -induced hepatitis and suppressed their phagocytic activities in vivo and in vitro. Macrophage and/or neutrophil depletion aggravated CCl4 -induced liver injury and impeded liver regeneration. Finally, conditional disruption of glucocorticoid receptor in macrophages and neutrophils abolished prednisolone-mediated exacerbation of hepatotoxin-induced liver injury. CONCLUSION Prednisolone treatment prevents T/NKT cell hepatitis but exacerbates hepatotoxin-induced liver injury by inhibiting macrophage- and neutrophil-mediated phagocytic and hepatic regenerative functions. These findings may not only increase our understanding of the steroid treatment mechanism but also help us to better manage steroid therapy in liver diseases.
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Affiliation(s)
- Hyo-Jung Kwon
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,College of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 305-764, South Korea
| | - Young-Suk Won
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, 363-883, South Korea
| | - Ogyi Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38:343-64. [PMID: 23808490 DOI: 10.1111/apt.12381] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig Dis Sci 2013; 58:1459-76. [PMID: 23306849 DOI: 10.1007/s10620-012-2525-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma and extrahepatic malignancies can complicate the course of autoimmune hepatitis, and these occurrences may increase in frequency as the survival of patients with cirrhosis is extended and the prospect of new nonstandard immune-modifying intervention is realized. The frequency of hepatocellular carcinoma in patients with autoimmune hepatitis and cirrhosis is 1-9 %, and annual occurrence in patients with cirrhosis is 1.1-1.9 %. The standardized incidence ratio for hepatocellular carcinoma in autoimmune hepatitis is 23.3 (95 % confidence interval (CI) 7.5-54.3) in Sweden, and the standardized mortality ratio for hepatobiliary cancer is 42.3 (95 % CI 20.3-77.9) in New Zealand. The principal risk factor is long-standing cirrhosis, and patients at risk are characterized mainly by cirrhosis for ≥ 10 years, manifestations of portal hypertension, persistent liver inflammation, and immunosuppressive therapy for ≥ 3 years. Multiple molecular disturbances, including the accumulation of senescent hepatocytes because of telomere shortening, step-wise accumulation of chromosomal injuries, and aberrations in transcription factors and genes, may contribute to the risk. Extraheptic malignancies of diverse cell types occur in 5 % in an unpredictable fashion. The standardized incidence ratio is 2.7 (95 % CI 1.8-3.9) in New Zealand, and non-melanoma skin cancers are most common. Outcomes are related to the nature and stage of the tumor at diagnosis. Surveillance recommendations have not been promulgated, but hepatic ultrasonography every six months in patients with cirrhosis is a consideration. Routine health screening measures for other malignancies should be applied diligently.
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Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol 2013; 7:365-85. [PMID: 23639095 DOI: 10.1586/egh.13.21] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African-American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian-American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Abstract
Autoimmune hepatitis frequently has an abrupt onset of symptoms, and it can present with acute liver failure. The abrupt presentation can indicate spontaneous exacerbation of a pre-existent chronic disease, newly created disease, a superimposed infectious or toxic injury, or new disease after viral infection, drug therapy, or liver transplantation. Deficiencies in the classical phenotype may include a low serum immunoglobulin G level and low or absent titers of the conventional autoantibodies. The original revised diagnostic scoring system of the International Autoimmune Hepatitis Group can guide the diagnostic evaluation, but low scores do not preclude the diagnosis. Liver tissue examination is valuable to exclude viral-related or drug-induced liver injury and support the diagnosis by demonstrating centrilobular necrosis (usually with interface hepatitis), lymphoplasmacytic infiltration, hepatocyte rosettes, and fibrosis. Conventional therapy with prednisone and azathioprine induces clinical and laboratory improvement in 68-75 % of patients with acute presentations, and high dose prednisone or prednisolone (preferred drug) is effective in 20-100 % of patients with acute severe (fulminant) presentations. Failure to improve or worsening of any clinical or laboratory feature within 2 weeks of treatment or worsening of a mathematical model of end-stage liver disease within 7 days justifies liver transplantation in acute liver failure. Liver transplantation for acute severe (fulminant) autoimmune hepatitis is as successful as liver transplantation for autoimmune hepatitis with a chronic presentation and other types of acute liver failure (patient survival >1 year, 80-94 %). Liver transplantation should not be delayed or superseded by protracted corticosteroid therapy or the empiric institution of nonstandard medications.
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