Autoimmune Hepatitis—Immunologically Triggered Liver Pathogenesis—Diagnostic and Therapeutic Strategies

Sucher, Elisabeth; Sucher, Robert; Gradistanac, Tanja; Brandacher, Gerald; Schneeberger, Stefan; Berg, Thomas

doi:10.1155/2019/9437043

Cited by 100 publications

(102 citation statements)

References 197 publications

(212 reference statements)

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“…AIH is mainly characterized by liver inflammation, which is essentially a chronic and unresolved liver inflammatory damage (6). Inflammation is an energy-expensive biological process that requires a large amount of energy and intermediary metabolites for the synthesis of inflammatory factors and immune response (7).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis

Niu

Jing

et al. 2021

Front. Med.

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Objectives: Autoimmune hepatitis (AIH) can progress into severe outcomes, i.e., decompensated cirrhosis, from remarkable and persistent inflammation in the liver. Considering the energy-expending nature of inflammation, we tried to define the metabolomics signatures of AIH to uncover the underlying mechanisms of cirrhosis development and its metabolic biomarkers.Methods: Untargeted metabolomics analysis was performed on sera samples from 79 AIH patients at the stages (phenotypes) of non-cirrhosis (n = 27), compensated cirrhosis (n = 22), and decompensated cirrhosis (n = 30). Pattern recognition was used to find unique metabolite fingerprints of cirrhosis with or without decompensation.Results: Out of the 294 annotated metabolites identified, 2 metabolic fingerprints were found associated with the development of cirrhosis (independent of the decompensated state, 42 metabolites) and the evolution of decompensated cirrhosis (out of 47 metabolites), respectively. The cirrhosis-associated fingerprints (eigenmetabolite) showed better capability to differentiate cirrhosis from non-cirrhosis patients than the aminotransferase-to-platelet ratio index. From the metabolic fingerprints, we found two pairs of metabolites (Mesobilirubinogen/6-Hydroxynicotinic acid and LysoPA(8:0/0:0)/7alpha-Hydroxycholesterol) calculated as ratio of intensities, which revealed robust abilities to identify cirrhosis or predict decompensated patients, respectively. These phenotype-related fingerprint metabolites featured fundamental energy supply disturbance along with the development of AIH cirrhosis and progression to decompensation, which was characterized as increased lipolysis, enhanced proteolysis, and increased glycolysis.Conclusions: Remodeling of metabolism to meet the liver inflammation-related energy supply is one of the key signatures of AIH in the development of cirrhosis and decompensation. Therefore, drug regulation metabolism has great potential in the treatment of AIH.

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Section: Introductionmentioning

confidence: 99%

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis

Niu

Jing

et al. 2021

Front. Med.

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“…Thus, we speculated that the elevated serum IgG4 levels observed during the pathogenesis of AIH may occur because of IgG4 binding to the PD-1 receptor on the surface of TH17 cells, which could block the PD-1 pathway-mediated inhibition of TH17 cell proliferation and cytokine generation, thereby promoting TH17 cell proliferation and increased production of related cytokines and causing the higher prevalence of cirrhosis observed in AIH patients with elevated serum IgG4 levels. Previous studies reported [ 6 , 7 ] that the increase in the number of TH17 cells in AIH was associated with the degree of liver fibrosis, and in vitro studies also confirmed that deficiencies in IL-17A and IL-17A receptors could reduce the liver fibrosis caused by CCl4 and bile duct ligation in mice [ 33 ]. Other studies [ 34 ] also showed that serum IL-17A and IL-22 levels were positively correlated with liver injury in AIH.…”

Section: Discussionmentioning

confidence: 68%

“…An existing study [ 6 ] suggests that interleukin (IL) 17 can stimulate a variety of types of nonparenchymal liver cells to secrete proinflammatory cytokines and chemokines to induce and promote liver inflammation in liver disease. IL-17 also promotes liver fibrosis by activating hepatic stellate cells [ 7 ]; therefore, we explored the differences in TH17-related cytokines between the elevated serum IgG4 group and the normal group.…”

Section: Resultsmentioning

confidence: 99%

“…Considering that studies on the clinical features and pathogenesis of AIH with elevated serum IgG4 levels are lacking, and some existing research [ 6 , 7 ] have pointed out that the degree of TH17 cells infiltration into the AIH liver is related to the degrees of liver inflammation and fibrosis, so this study assessed the clinical features of AIH with elevated serum IgG4 levels and the possible role of TH17 cells in the pathogenesis of this disease.…”

Section: Introductionmentioning

confidence: 99%

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Autoimmune Hepatitis with Elevated Serum IgG4 Levels Have a High Prevalence of Cirrhosis at Diagnosis

Xue

Shen

Fan

et al. 2021

Canadian Journal of Gastroenterology and Hepatology

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Background. Some autoimmune hepatitis (AIH) patients have elevated serum IgG4 levels, and the clinical characteristics of such patients are currently incompletely characterized. Aim. To analyze the clinical features and possible pathogenesis of AIH with elevated serum IgG4 levels. Methods. According to their serum IgG4 value, patients were divided into elevated IgG4 (IgG4 > 1.35 g/l) and normal IgG4 (IgG4 ≤ 1.35 g/l) groups. Results. Among the 152 patients included in this study, those in the elevated IgG4 group had the following characteristics: older onset age (56 ± 11.43 years vs. 49.49 ± 13.04 years, P = 0.005 ), higher proportion of males (34.15% vs. 12.61%, P = 0.002 ), higher prevalence of cirrhosis (56.10% vs. 36.04%, P = 0.026 ), lower prevalence of extrahepatic autoimmune diseases (9.76% vs. 27.3%, P = 0.023 ), and higher levels of IL-17 and IL-22 ( P < 0.05 ). Logistic regression analysis results showed that elevated serum IgG4 levels and male sex were risk factors for AIH cirrhosis (male: odds ratio (OR) = 4.293, 95% confidence interval (CI): 1.592–11.575, P = 0.004 ; and elevated serum IgG4: OR = 2.566, 95% CI: 1.065–6.187, P = 0.036 ). No significant differences were found for the remission rate within 6 months between the two groups (69.70% vs. 76.14%, P = 0.470 ). Conclusion. The male proportion and cirrhosis prevalence were higher in AIH with elevated serum IgG4 levels at the time of diagnosis. Male sex and elevated serum IgG4 levels are independent risk factors for AIH cirrhosis, and TH17 cells are more likely involved in the pathogenesis of this type of AIH.

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“…Immune cells that accumulated in the portal/periportal lesions were composed of CD4 + T cells, CD8 + T cells, CD20 + B cells, CD138 + plasma cells and FOXP3 + Tregs. Thus, various adaptive immune cells infiltrate the portal and periportal lesions of patients with AIH, suggesting that maturation of immune networks in the portal tract is necessary for the development of AIH 33 . In addition, CD4 + T cells and CD20 + B cells accumulated into the lobular lesions of patients with AIH, but not hepatic irAEs or GVHD.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease

Hagiwara

Watanabe

Kudo

et al. 2021

Sci Rep

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Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.

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Autoimmune Hepatitis—Immunologically Triggered Liver Pathogenesis—Diagnostic and Therapeutic Strategies

Cited by 100 publications

References 197 publications

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis

Autoimmune Hepatitis with Elevated Serum IgG4 Levels Have a High Prevalence of Cirrhosis at Diagnosis

Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease

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