Total glucosides of paeony decreases apoptosis of hepatocytes and inhibits maturation of dendritic cells in autoimmune hepatitis.

Total glucosides of paeony (TGP), an active mixture extracted from paeony root, has anti-inflammatory and immunoregulatory effects and is widely used for the treatment of autoimmune diseases such as rheumatoid arthritis. However, the role of TGP in autoimmune hepatitis (AIH) is still unknown. In this study, we aimed to investigate the effect of TGP in autoimmune liver disease (AILD) patients and in concanavalin A (Con A)-induced experimental autoimmune hepatitis (EAH). Changes in biochemical parameters of AILD patients showed that treatment with TGP exerts significant protective effects on liver function, as reflected by decreased levels of serum alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase and total bilirubin. In EAH mice, we found that pretreatment with TGP reduced the levels of serum liver enzyme levels, histopathological damage and hepatocyte apoptosis. Importantly, flow cytometry analysis showed that pretreatment with TGP reduced the infiltration of mature dendritic cells in the liver. In vitro, TGP pretreatment ameliorated the Con A-induced mitochondrial membrane potential decline, reactive oxygen species increase, and apoptosis increase in hepatocytes. In addition, the levels of Bax, Cleaved Caspase-3 and cytoplasmic Cytochrome C decreased during this process, whereas those of Bcl-2 and mitochondrial Cytochrome C increased. Therefore, TGP might decrease hepatocyte apoptosis through the mitochondrial apoptotic pathway. Moreover, the maturation of bone marrow dendritic cells was also inhibited by TGP treatment. In conclusion, TGP treatment ameliorates AIH by regulating hepatocyte apoptosis and DC maturation. TGP is a potential compound for AIH treatment.

Autoimmune Hepatic Failure Following Acute Hepatitis A is Accompanied by Inflammatory Conversion of Regulatory T Cells.

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, we performed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantation due to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remained high for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells into mediators of inflammation may have played a role in the autoimmune pathogenesis following AHA.

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

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.

Characteristics and outcome of primary sclerosing cholangitis associated with inflammatory bowel disease in Asian children.

BACKGROUND: Current knowledge on the clinical features and natural history of childhood primary sclerosing cholangitis - inflammatory bowel disease in Asia is limited. We described the presenting features and natural history of primary sclerosing cholangitis-inflammatory bowel disease seen in a cohort of Southeast Asian children. METHODS: We conducted a retrospective review of childhood primary sclerosing cholangitis-inflammatory bowel disease from three tertiary centers in Singapore and Malaysia. RESULTS: Of 24 patients (boys, 58%; median age at diagnosis: 6.3 years) with primary sclerosing cholangitis-inflammatory bowel disease (ulcerative colitis, n = 21; Crohn's disease, n = 1; undifferentiated, n = 2), 63% (n = 15) were diagnosed during follow-up for colitis, and 21% (n = 5) presented with acute or chronic hepatitis, 17% (n = 4) presented simultaneously. Disease phenotype of liver involvement showed 79% had sclerosing cholangitis-autoimmune hepatitis overlap, 54% large duct disease, and 46% small duct disease. All patients received immunosuppression therapy. At final review after a median [±S.D.] duration follow-up of 4.7 [±3.8] years, 12.5% patients had normal liver enzymes, 75% persistent disease, and 12.5% liver failure. The proportion of patients with liver cirrhosis increased from 13% at diagnosis to 29%; 21% had portal hypertension, and 17% had liver dysfunction. One patient required liver transplant. Transplant-free survival was 95%. For colitis, 95% had pancolitis, 27% rectal sparing, and 11% backwash ileitis at initial presentation. At final review, 67% patients had quiescent bowel disease with immunosuppression. One patient who had UC with pancolitis which was diagnosed at 3 years old developed colorectal cancer at 22 years of age. All patients survived. CONCLUSIONS: Liver disease in primary sclerosing cholangitis-inflammatory bowel disease in Asian children has variable severity. With immunosuppression, two-thirds of patients have quiescent bowel disease but the majority have persistent cholangitis and progressive liver disease.

Autoimmune Hepatitis A Case Report and Literature Review.

INTRODUCTION: Autoimmune hepatitis (AIH) is a cause of chronic liver disease. It is usually suspected based on clinical presentation and laboratory findings, but the diagnosis relies on the presence of specific autoantibodies and characteristic histology. Other unexplained findings should always prompt investigation for coexisting syndromes. CASE PRESENTATION: The patient is a 60-year-old Hispanic female with a history of mild asthma presented with exertional and pleuritic chest pain with weight loss, arthralgia, subjective fever, and night sweats for the last 3 months. Given the nonspecific nature of the presentation, further workup was pursued. Laboratory results indicated pancytopenia, elevated INR, and positive autoimmune panel including ANA, anti-chromatin, anti-histone, and rheumatoid factor as well as abnormal C3 and C4. Subsequent liver biopsy with interface hepatitis lead to a diagnosis of AIH with concurrent systemic lupus erythematosus suspected. CONCLUSION: The diagnostic work up for AIH is multimodal and aims to differentiate other etiologies such as congestive hepatopathy, iron overload, viral hepatitis, and other autoimmune liver diseases. In this particular case, unusual clinical and laboratory findings led to diagnosis of the overlap syndrome. Treatment for both was necessary to prevent further progression of disease.

Frequency of Hepatobiliary Manifestations and Concomitant Liver Disease in Inflammatory Bowel Disease Patients.

BACKGROUND: In inflammatory bowel disease (IBD) patients there are reports of the occurrence of hepatobiliary manifestations, so the aim of this study was to evaluate the hepatobiliary manifestations in patients with Crohn's disease (CD) and ulcerative colitis (UC) from an IBD reference center. METHODS: Cross-sectional study in an IBD reference center, with interviews and review of medical charts, between July 2015 and August 2016. A questionnaire addressing epidemiological and clinical characteristics was used. RESULTS: We interviewed 306 patients, and the majority had UC (53.9%) and were female (61.8%). Hepatobiliary manifestations were observed in 60 (19.6%) patients with IBD. In the greater part of the patients (56.7%) hepatobiliary disorders were detected after the diagnosis of IBD. In UC (18.2%) patients, the hepatobiliary disorders identified were 11 (6.7%) non-alcoholic fatty liver disease, 9 (5.5%) cholelithiasis, 6 (3.6%) primary sclerosing cholangitis (PSC), 3 (1.8%) hepatotoxicity associated with azathioprine, 1 (0.6%) hepatitis B, and 1 (0.6%) hepatic fibrosis. In CD (21.3%) patients, 11 (7.8%) had cholelithiasis, 11 (7.8%) non-alcoholic fatty liver disease, 4 (2.8%) PSC, 3 (2.1%) hepatotoxicity, 1 (0.7%) hepatitis B, (0.7%) hepatitis C, 1 (0.7%) alcoholic liver disease, and 1 (0.7%) autoimmune hepatitis (AIH). There was one case of PSC/AIH overlap syndrome. CONCLUSION: The frequency of hepatobiliary disorders was similar in both forms of IBD in patients evaluated. The most common nonspecific hepatobiliary manifestations in IBD patients were non-alcoholic liver disease and cholelithiasis. The most common specific hepatobiliary disorder was PSC in patients with extensive UC or ileocolonic CD involvement; this was seen more frequently in male patients.

Clinical presentation of autoimmune hepatitis in Pakistani children.

INTRODUCTION: Autoimmune hepatitis (AIH) is one of the most common disorder resulting in end stage liver disease (ESLD) among children. Scarce data is available in this regard from Pakistan. In this study we have analyzed clinical and biochemical parameters of children suffering from this disorder. METHODS: It was a cross sectional study conducted in the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT) Karachi from January 2005 to June 2016. Patients aged up-to 18 years were included. AIH was diagnosed by using International Autoimmune hepatitis group (IAIHG) pre-treatment and simplified AIH score. Patients with both probable and definite score were included. Biochemical, serological, sonographic and demographics were recorded at the time of diagnosis, liver biopsy was also performed in most of the cases. Data was analyzed by using SPSS ver.20 and p-value of < 0.05 was considered significant. RESULTS: Total 51 patients were enrolled most of them were females (68.6%). Mean age of presentation was around 10 years. Males had statistically significant earlier age of presentation, p-value = 0.007. The most common presenting complain was jaundice. Hypergammaglobulinemia is seen in almost all patients. Type I AIH was the most common entity while Type II AIH was statistically more significant in males p-value = 0.019. Raised GGT was also seen in male patient specifically in Type II AIH, p-value = 0.001. CONCLUSION: Autoimmune hepatitis predominantly affects female children who have late age of presentation as compare to the males. Type I AIH was the most common while Type II AIH was more common in males and they also had raised GGT.

Autoimmune hepatitis.

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.

Current and future perspectives in autoimmune hepatitis.

Autoimmune hepatitis occurs in genetically susceptible individuals as a result of loss of immunological tolerance to hepatic autoantigens that can be precipitated by environmental triggers. The clinical manifestation is usually insidious but can be also acute with liver failure. The diagnosis is made on the basis of antibody positivity, elevated immunoglobulin G levels and interface hepatitis on liver histology. Induction of remission is achieved with high-dose steroids in the majority of cases, and maintenance of remission with azathioprine. Treatment withdrawal is achievable only in a small proportion of patients. Patients with acute liver failure unresponsive to steroids or those with end-stage liver failure or hepatocellular carcinoma may require liver transplantation. Variant forms of overlapping autoimmune hepatitis with either primary biliary cholangitis or sclerosing cholangitis are associated with worse outcomes. New insights into the pathophysiology of the disease may provide novel therapeutic targets and a more individualized approach to treatment of autoimmune hepatitis.

Anti-TNFα Treatment in Children and Adolescents With Combined Inflammatory Bowel Disease and Autoimmune Liver Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) and autoimmune liver disease (AILD) are closely associated, the former often dictating progression of the latter. Antibodies to tumor necrosis factor alpha (anti-TNFα) are effective in the management of IBD, but may cause liver injury. METHODS: Retrospective review of medical records of patients with juvenile AILD who received anti-TNFα for IBD to evaluate the safety and efficacy of anti-TNFα. RESULTS: Eleven patients (6 boys), ages 9 to 15 years (median 13 years) were identified. Ten had ulcerative colitis and 1 Crohn disease; 2 had autoimmune hepatitis type 1 and 9 autoimmune hepatitis-sclerosing cholangitis variant. All patients were started on infliximab (IFX, 5 mg/kg) and 2 required dose increase (10 mg/kg); 3 of 11 switched to adalimumab due to allergic reaction or nonresponse. Three received adalimumab after losing response or developing antibodies to IFX. Liver function tests (LFTs) improved in 5, 1 continued to have stably abnormal LFTs and 2 maintained normal LFTs. Patients on adalimumab showed stable or improved liver function compared to pretreatment status. Six of 8 treated with a full course of IFX maintained clinical remission of IBD for 6 months to 2.5 years; of the 6 patients treated with adalimumab, 1 sustained IBD clinical remission for 24 months, 2 achieved remission only after tacrolimus addition and 3 did not respond. CONCLUSIONS: IBD in patients with AILD can be aggressive, requiring escalation to anti-TNFα or switching to other biologics. In this series, anti-TNFα did not impair liver function and improved gut disease in most of the patients, indicating that it can be beneficial and safe.

Involvement of the Nrf2/HO-1/CO axis and therapeutic intervention with the CO-releasing molecule CORM-A1, in a murine model of autoimmune hepatitis.

Concanavalin A (ConA)-induced hepatitis is an experimental model of human autoimmune hepatitis induced in rodents by i.v. injection of Con A. The disease is characterized by increase in serum levels of transaminases and massive immune infiltration of the livers. Type 1, type 2, and type 17 cytokines play a pathogenic role in the development of ConA-induced hepatitis. To understand further the immunoregulatory mechanisms operating in the development and regulation of ConA-induced hepatitis, we have evaluated the role of the anti-inflammatory pathway Nrf2/HO-1/CO (Nuclear Factor E2-related Factor 2/Heme Oxygenase-1/Carbon Monoxide) in this condition and determined whether the in vivo administration of CO via the CO-releasing molecule (CORM) CORM-A1, influences serological and histological development of Con-A-induced hepatitis. We have firstly evaluated in silico the genes belonging to the Nrf2/HO-1/CO pathway that are involved in the pathogenesis of autoimmune hepatitis (AIH). The data obtained from the in silico study demonstrate that a significant number of genes modulated in the liver of ConA-challenged mice belong to the Nrf2 pathway; on the other hand, the administration of CORM-A1 determines an improvement in several sero-immunological and histological parameters, and it is able to modulate genes identified by the in silico analysis. Collectively, our data indicate that the Nrf2/HO-1/CO pathway is fundamental for the regulation of the immune responses, and that therapeutic intervention aimed at its modulation by CORM-A1 may represent a valuable strategy to be considered for the treatment of autoimmune hepatitis in humans.

Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation.

Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).

Histopathology of IgG4-Related Autoimmune Hepatitis and IgG4-Related Hepatopathy in IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease involving many organs; it includes IgG4-related sclerosing cholangitis and inflammatory pseudotumor in the hepatobiliary system. Two types of hepatic parenchymal involvement have been reported in IgG4-RD: IgG4-related autoimmune hepatitis (AIH) and IgG4-hepatopathy. Moreover, only three cases of IgG4-related AIH have been reported. Immunoglobulin G4-related AIH is clinicopathologically similar to AIH, except for an elevated serum IgG4 level and heavy infiltration of IgG4-positive plasma cells in the liver tissue. Interestingly, IgG4-related AIH can be complicated by well-known IgG4-RD(s). Immunoglobulin G4-hepatopathy, which includes various histopathological lesions encountered in the liver of patients with type I autoimmune pancreatitis, is classified into five histological categories: portal inflammation, large bile duct damage, portal sclerosis, lobular hepatitis, and cholestasis. Immunoglobulin G4-hepatopathy is currently a collective term covering hepatic lesions primarily or secondarily related to IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis. In conclusion, the liver is not immune to IgG4-RD, and at least two types of hepatic involvement in IgG4-RD have been reported: IgG4-related AIH and IgG4-hepatopathy. Additional studies are required to clarify their precise clinical significance with respect to IgG4-RD and inherent liver diseases.

A serum metabolomic analysis for diagnosis and biomarker discovery of primary biliary cirrhosis and autoimmune hepatitis.

BACKGROUND: Because of the diversity of the clinical and laboratory manifestations, the diagnosis of autoimmune liver disease (AILD) remains a challenge in clinical practice. The value of metabolomics has been studied in the diagnosis of many diseases. The present study aimed to determine whether the metabolic profiles, based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), differed between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), to identify specific metabolomic markers, and to establish a model for the diagnosis of AIH and PBC. METHODS: Serum samples were collected from 20 patients with PBC, 19 patients with AIH, and 25 healthy individuals. UPLC-MS data of the samples were analyzed using principal component analysis, partial least squares discrimination analysis and orthogonal partial least squares discrimination analysis. RESULTS: The partial least squares discrimination analysis model (R2Y=0.991, Q2=0.943) was established between the AIH and PBC groups and exhibited both sensitivity and specificity of 100%. Five groups of biomarkers were identified, including bile acids, free fatty acids, phosphatidylcholines, lysolecithins and sphingomyelin. Bile acids significantly increased in the AIH and PBC groups compared with the healthy control group. The other biomarkers decreased in the AIH and PBC groups compared with those in the healthy control group. In addition, the biomarkers were downregulated in the AIH group compared with the PBC group. CONCLUSIONS: The biomarkers identified revealed the pathophysiological changes in AILD and helped to discriminate between AIH and PBC. The predictability of this method suggests its potential application in the diagnosis of AILD.

In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression.

UNLABELLED: Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory T-cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4(+) CD25(+) or CD4(+) CD25(high) cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4(+) CD25(+) CD127(-) Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona-fide Tregs produce less interleukin (IL)-10 and are impaired in their ability to suppress CD4(+) CD25(-) target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL-10 secretion. Decreased IL-10 production by Tregs in AILD is linked to poor responsiveness to IL-2 and phospho signal transducer and activator of transcription 5 up-regulation. CONCLUSION: Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL-10 production, resulting from low Treg responsiveness to IL-2, contributes to Treg functional impairment.