Treatment Of Autoimmune Liver Diseases Research Articles

M1 macrophage-derived exosomes promote autoimmune liver injury by transferring long noncoding RNA H19 to hepatocytes.

Exosomes mediate intercellular communication by transmitting active molecules. The function of long noncoding RNA (lncRNA) H19 in autoimmune liver injury is unclear. Concanavalin A (ConA)-induced liver injury is well-characterized immune-mediated hepatitis. Here, we showed that lncRNA H19 expression was increased in the liver after ConA treatment, accompanied by increased exosome secretion. Moreover, injection of AAV-H19 aggravated ConA-induced hepatitis, with an increase in hepatocyte apoptosis. However, GW4869, an exosome inhibitor, alleviated ConA-induced liver injury and inhibited the upregulation of lncRNA H19. Intriguingly, lncRNA H19 expression in the liver was significantly downregulated, after macrophage depletion. Importantly, the lncRNA H19 was primarily expressed in type I macrophage (M1) and encapsulated in M1-derived exosomes. Furthermore, H19 was transported from M1 to hepatocytes via exosomes, and exosomal H19 dramatically induced hepatocytes apoptosis both in vitro and vivo. Mechanistically, H19 upregulated the transcription of hypoxia-inducible factor-1 alpha (HIF-1α), which accumulated in the cytoplasm and mediated hepatocyte apoptosis by upregulating p53. M1-derived exosomal lncRNA H19 plays a pivotal role in ConA-induced hepatitis through the HIF-1α-p53 signaling pathway. These findings identify M1 macrophage-derived exosomal H19 as a novel target for the treatment of autoimmune liver diseases.

SAT-372 - Developing highly pure, functional GMP grade Treg for the treatment of autoimmune liver disease

SAT-372 - Developing highly pure, functional GMP grade Treg for the treatment of autoimmune liver disease

Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases?

Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases?

Dietary Polyphenols Alleviate Autoimmune Liver Disease by Mediating the Intestinal Microenvironment: Challenges and Hopes.

Autoimmune liver disease is a chronic liver disease caused by an overactive immune response in the liver that imposes a significant health and economic cost on society. Due to the side effects of existing medicinal medications, there is a trend toward seeking natural bioactive compounds as dietary supplements. Currently, dietary polyphenols have been proven to have the ability to mediate gut-liver immunity and control autoimmune liver disease through modulating the intestinal microenvironment. Based on the preceding, this Review covers the many forms of autoimmune liver illnesses, their pathophysiology, and the modulatory effects of polyphenols on immune disorders. Finally, we focus on how polyphenols interact with the intestinal milieu to improve autoimmune liver disease. In conclusion, we suggest that dietary polyphenols have the potential as gut-targeted modulators for the prevention and treatment of autoimmune liver disease and highlight new perspectives and critical issues for future pharmacological applications.

Celebrate the centennial of the Communist Party of China by making contributions to Healthy China:The official release of China's first guidelines for diagnosis and treatment of autoimmune liver diseases

自身免疫性肝病是因自身免疫紊乱导致肝脏细胞受损而产生的慢性肝病，主要包括自身免疫性肝炎、原发性胆汁性胆管炎、原发性硬化性胆管炎和IgG4相关硬化性胆管炎等。2015年，中华医学会肝脏病学分会针对自身免疫性肝炎、原发性胆汁性胆管炎、原发性硬化性胆管炎和胆汁淤积性肝病分别推出了诊疗共识，这是我国自身免疫性肝病临床诊治的重要里程碑事件。近年来，国内外研究进展迅速，有必要以更高的循证标准制定疾病指南，为疾病的规范化诊治提供依据和准则。2021年7月，中华医学会肝脏病学分会自身免疫性肝病学组召开学术年会，会议期间举行了自身免疫性肝病指南撰写启动会。经过多次讨论和修改，于2021年12月首发于《中华内科杂志》。.

Antigen-Specific Immunotherapy for Treatment of Autoimmune Liver Diseases.

The liver is a critical organ in controlling immune tolerance. In particular, it is now clear that targeting antigens for presentation by antigen presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or tissues outside of the liver. Here we review immune mechanisms active within the liver that contribute both to the control of infectious diseases and tolerance to self-antigens. Despite its extraordinary capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. In this review, we compare and contrast known autoimmune diseases of the liver. Currently patients tend to receive strong immunosuppressive treatments and, in many cases, these treatments are associated with deleterious side effects, including a significantly higher risk of infection and associated health complications. We propose that, in future, antigen-specific immunotherapies are adopted for treatment of liver autoimmune diseases in order to avoid such adverse effects. We describe various therapeutic approaches that either are in or close to the clinic, highlight their mechanism of action and assess their suitability for treatment of autoimmune liver diseases.

The Contribution of B Cells in Autoimmune Liver Diseases

Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.

Research advances of autoimmune liver diseases in 2018

Autoimmune liver disease is a group of hepatobiliary injuries mediated by abnormal immunity. It mainly includes autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. Recently, an advancement of diagnostic technology has improved the detection and treatment of autoimmune hepatitis. However, it is easy to be confused with other liver diseases. Thus, the standardization of diagnosis and treatment of autoimmune liver diseases has become a main concern. Moreover, new progress has been made in basic research and clinical treatment of autoimmune liver diseases since 2018. In this review, we have introduced the latest research advances for the diagnosis and treatment of autoimmune liver diseases.

Management of patients with autoimmune liver diseases on the basis of the latest EASL recommendations and our own experience (lecture to a practical doctor)

Autoimmune hepatitis (AIH), primary biliary cirrhosis/cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangiopaties are the autoimmune liver diseases. These diseases are rare and remain under-explored, therefore difficult for understanding and conducting even by specialists. Aim. To provide a comprehensively modern view of autoimmune liver diseases and their features. It is important to clearly distinguish AIG, PBH, and PSC between each other. Epidemiological data indicate low prevalence of these diseases, but its growth is noted. Most of the patients are young and middle age, prevalence of the AIH and PBC is higher in women, for PSC - in men. Etiologic factors remain unknown; the role of viral-bacterial, toxic, drugs that change the immune system with forming of autoantibodies is examined. Genetic factors also may play role in pathogenesis of these diseases. Diagnostics of autoimmune liver diseases are based on specific signs. AIH can proceed as acute or chronic hepatitis, cirrhosis or fulminant hepatic-cellular insufficiency, but also can be asymptomatic for a long time. For PBC and PSC, the clinic of cholestasis is characterized by skin itch, jaundice, skin changes. In later stages, a picture of cirrhosis develops. Hepatic tests in patients with AIH are characterized by predominance of cytolysis that can reach high values, and for PBC and PSC – cholestasis with high alkaline phosphatase and GGTP.Diagnostics with specific markers of autoimmune liver diseases are crucial for our country. AIH is characterized by detection of ANA, SMA, anti-LKM, anti-SLA, anti-LP anti-LC1, ASGP-R, and increased level of IgG. A highly specific PBC marker is AMA-M2, while p-ANCA can be determined in PSC.Among the visualizing methods of the hepatobiliary system, MRCP was identified as an accurate method for evaluating the duct system in PSC and liver elastography for evaluating the degree of fibrosis.Treatment of autoimmune liver diseases, according to the latest EASL recommendations, includes immunosuppressive therapy with hormones, azathioprine, other cytostatics, UDCA. Since the data of evidence-based medicine are limited, it is believed that an expert opinion can be crucial for the treatment of such patients. Clinical examples showing the features of management of autoimmune liver diseases are given in this article.Conclusions. Diagnosis and treatment of autoimmune liver diseases are a complex process. In this case, the latest modern recommendations can considerably help, at the same time, the clinical experience of the doctor and the patient’s individual data still matter.

Protective effects of artesunate against Con A-induced autoimmune liver injury in mice

Autoimmune liver disease is a refractory disease clinically, and there is no particularly effective drug at present. Therefore, it is of important clinical value to develop new effective intervention drugs for the prevention and treatment of autoimmune liver disease. In order to investigate the potential protective effect of artesunate (Art) on concanavalin A (Con A)-induced autoimmune liver injury, different doses of Art (27, 54, 108 mg·kg⁻¹) were orally administered to mice for consecutive 7 days, respectively. Then the Con A was injected into mice via tail vein to induce liver injury models. 8 h after modeling, the mice were sacrificed. The serum and liver tissue were collected for detecting the level of alanine aminotransferase (ALT), and aspartate transaminase (AST), liver pathological histopathology, inflammatory cytokines and nuclear factor (NF-κB) key protein expression level. The results showed that 108 mg·kg⁻¹ Art remarkably reduced Con A-induced liver indexes and serum transaminase levels (ALT and AST) as compared with model group(P<0.01). Meanwhile, the liver histopathological changes were obviously alleviated with a significant decrease of pro-inflammatory cytokine including tumor necrosis factor (TNF-α), interferon (IFN-γ), interleukin (IL-6), IL-17 and a higher increase of anti-inflammatory cytokine IL-10 (P<0.01). Western blot results showed that 108 mg·kg⁻¹ Art markedly inhibited the expressions of p-p65 and p-IκBα proteins (P<0.01). The specific inhibitor of NF-κB, pyrrolidinedithiocarbamate (PDTC) could also significantly inhibit the expressions of p-p65 and p-IκBα with and alleviate liver injuries. Therefore, our results indicated that Art may have a protective action against Con A-induced autoimmune liver injury mainly by suppressing NF-κB signal pathway in mice. The study provides scientific reference for artesunate usage in preventing autoimmune liver injury.

Prevalence and “real-life” treatment of autoimmune liver diseases in Germany

Prevalence and “real-life” treatment of autoimmune liver diseases in Germany

Research advances in autoimmune liver diseases in 2016

Autoimmune liver diseases are a group of abnormal autoimmune-mediated inflammatory hepatobiliary injuries, mainly including autoimmune hepatitis(AIH), primary biliary cholangitis(PBC), and primary sclerosing cholangitis (PSC). The diagnosis and treatment of autoimmune liver diseases, an important type of non-viral liver disease, have become a prominent issue in hepatology. In 2016, many new advances have been achieved in the clinical and basic research on autoimmune liver diseases, including the phase 3 clinical trial of obeticholic acid, the proposal of UK-PBC risk score, and the research on gut microbiota associated with PSC. This article reviews the research advances in the diagnosis and treatment of autoimmune liver diseases in 2016.

SAT-376 - A population based analysis of prevalence and treatment of autoimmune liver diseases in Germany

SAT-376 - A population based analysis of prevalence and treatment of autoimmune liver diseases in Germany

Diagnosis and Treatment of Autoimmune Liver Diseases in a Tertiary Referral Center in Cuba

BackgroundAutoimmune liver diseases (AILD) comprise a set of entities characterized by tissue damage as a result of the loss of self-tolerance. There are few reports of AILD from Caribbean countries. ObjectivesThe aim of our study was to investigate the clinical patterns, laboratory findings, and immunologic features, treatment responses, and prognoses of AILD in adult patients at a Cuban tertiary referral center. MethodsA prospective study was conducted at the National Institute of Gastroenterology in Havana, Cuba, from May 2012 to April 2016. Clinical, immunologic, and histologic features of autoimmune hepatitis (AIH), primary biliary cirrhosis, AIH/primary biliary cirrhosis overlap syndrome, autoimmune cholangiopathy, and primary sclerosing cholangitis were recorded. Response to therapy was assessed by serum alanine aminotransferase and bilirubin levels at 3, 6, 12, and 24 months after treatment initiation. ResultsOf the 106 patients included in the study, 85.5% were women. The median age at presentation was 47 years. AIH was the most common AILD and was diagnosed in 60 patients (56.6%), 55 of whom had type 1 AIH. Primary biliary cirrhosis was diagnosed in 22 patients (20.7%), overlap syndrome in 16 patients (15%), autoimmune cholangiopathy in 5 patients (4.71%), and PSC in 3 patients (2.8%). Most patients were symptomatic; 48 patients (45.2%) presented with liver cirrhosis, 14.5% of whom had decompensated cirrhosis. Follow-up of treatment was between 6 and 24 months. Prednisone monotherapy was used in 22 AIH patients (36.6%) and a combination of prednisone and azathioprine was used in 28 (46.6%) AIH patients. Response to treatment was seen in 41 AIH patients (68.3%), 33 of whom (55%) had a complete response and 8 of whom (24.2%) relapsed after 12 months of maintenance therapy. No or incomplete response to treatment was seen in 18 patients (30%). In 46 patients with autoimmune cholestasis, ursodeoxycholic acid was used as monotherapy in 25 patients (54.3%). ConclusionsThe clinical profile of AILD in a sample of the Cuban population is similar to that reported in South areas (Developing countries). AIH was more frequent than PBC, and usually presented with advanced liver disease that responded poorly to treatment.

Liver Diseases and Autoimmunity.

Based on the principal clinical and pathological features, autoimmune diseases can be broadly divided into localized (involving only a single organ or tissue) and systemic (involving multiple organs). The liver is a lymphoid organ that not only participates in the immune response, but also a target of autoimmune reactions. Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are three major types of autoimmune diseases localized in the liver or autoimmune liver diseases, whereas granulomatous diseases such as sarcoidosis and connective tissue diseases such as systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren syndrome (PSS) are the major systemic autoimmune diseases with liver involvement. Over the past decade, advances have been achieved in the diagnosis and treatment of autoimmune liver diseases and liver involvement in systemic autoimmune diseases.1–5 Accordingly, in this issue of Journal of Clinical Translational Hepatology, the aim of the review articles is to update the knowledge and current management of autoimmune liver diseases and liver involvement in systemic autoimmune diseases. AIH is a chronic inflammatory liver disease of unknown cause, with an estimated prevalence of 0.5–1.0 per 100,000; it is more common in women than in men. There have been extensive studies on this important disease, and remission of the disease is now achievable by immunosuppression; however, the prognosis is very poor if the patients are left untreated. In this issue, Kapila et al. present the clinical manifestations of AIH, update pathogenesis of liver-directed immune injury and new concepts in the understanding of immune tolerance, and finally provide insight into the development of novel therapeutic approaches.6 Sarcoidosis is a systemic, granulomatous disease that usually affects multiple organs including the liver. The estimated prevalence of sarcoidosis is 2–60 per 100,000. So far, little is unknown about its etiology. Liver involvement in sarcoidosis is very common. In this issue, Tadros et al. introduce the epidemiology and clinical spectrum of hepatic sarcoidosis of the disease and explore the underlying mechanism for liver injury in hepatic sarcoidosis.7 Moreover, they provide state-of-the-art knowledge on the diagnosis, differential diagnosis (with PBC and PSC) and treatment of the disease. PSS is a systemic autoimmune disorder with secretory gland dysfunction. The estimated prevalence is 0.1–3.3%, with significant female preponderance, and it is reportedly associated with increased risk of cancers. Liver involvement is one of the commonly reported extraglandular manifestations of PSS, and two main causes of liver disease, namely chronic viral infections and autoimmune liver diseases contribute to liver involvement in PSS. Diagnosis of the causes of liver involvement in PSS is very important but challenging. In this issue, Briton-Zeron et al. 8 specifically describe the causes, and provide the diagnostic strategy accordingly. There is no doubt that the new data provided in this issue will enrich our understanding and improve clinical treatment of autoimmune liver diseases and liver involvement in systemic autoimmune diseases. This is consistent with the objective of Journal of Clinical Translational Hepatology to deliver recent advances in pathogenetic mechanisms, and developments in basic, translational and clinical studies.

Low Serum Hepcidin in Patients with Autoimmune Liver Diseases.

Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients’ sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.

Treatment of autoimmune liver disease: current and future therapeutic options

Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice.

Improving the diagnosis and treatment of autoimmune liver diseases

病毒性肝炎特别是乙型肝炎一直是我国肝脏疾病的主要病因.然而,自1992年开始推广新生儿普遍接种乙型肝炎疫苗以来,我国人群中HBsAg阳性率已从1992年的9.8%下降到2006年的7.2%[1-3].

Stem cell transplantation in the treatment of gastrointestinal diseases

The stem cells with self-renewal ability are capable to form one or more cell types. They will be in the target of cell and gene therapy because of their multipotency and easy retrieval. Application of adult mesenchymal, neuronal, epidermal and haematopoietic stem cell can be favourable in the treatment of cardiac (myocardial infarction), bone (osteoarthritis), neurological (Parkinson's, Alzheimer's) and hematological (hemophilia, thrombocytopenia) disorders. Authors summarize the knowledge in connection with their application in the therapy of gastrointestinal diseases. Haematopoietic stem cell transplantation has been successful for the treatment of refractory Crohn's disease, as well as in selected group of celiac patients. Mesenchymal stem cell transplantation has been proved beneficial in the prevention of liver fibrotic process. It will gain more grounds in the treatment of autoimmune liver diseases: autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis in the future. Well-designed, multicentric, prospective studies are needed to confirm the results of case reports and clinical studies with small group of patients.

Mycophenolate Mofetil in Autoimmune Hepatitis Patients Not Responsive or Intolerant to Standard Immunosuppressive Therapy

The immunosuppressive treatment for autoimmune hepatitis (AIH) patients is prednisone and azathioprine. Ten percent to 20% of patients do not respond or are intolerant of standard treatment. The aim of this study was to assess the biochemical, histologic, and hematologic parameters during mycophenolate mofetil (MMF) treatment in AIH patients who did not respond to or were intolerant of prednisone and/or azathioprine. A retrospective study was performed of 15 AIH patients who received MMF either as monotherapy or in combination with prednisone after failure or intolerance of the initial regimen. Records were reviewed as to initial therapy, reasons why MMF was initiated, liver enzyme levels, histology on MMF, and complications. The mean age was 60 +/- 15 years. All patients were started on MMF at 1 gram twice a day, 3 on MMF monotherapy, and 12 on prednisone and MMF. The average MMF treatment duration was 41 months. Alanine aminotransferase levels decreased significantly from 91.73 +/- 88.69 to 60.87 +/- 71.2 (P = .03) on MMF treatment. Inflammatory scores (2.59 +/- 0.97 to 1.14 +/- 1.21, P = .02) and Ishak fibrosis scores (4.10 +/- 1.37 to 2.5 +/- 1.51, P = .02) also decreased. No significant hematologic complications were noted during MMF treatment. Administration of MMF, either as monotherapy or in combination with prednisone, results in biochemical and histologic improvement in AIH patients who are prednisone and/or azathioprine intolerant or resistant without the development of significant complications. MMF should be studied prospectively as an alternative agent in the treatment of autoimmune liver disease.