Treatment Of Autoimmune Hepatitis Research Articles

Graves\u2019 disease overlapping with chronic hepatitis B and methimazole-induced liver injury and autoimmune hepatitis: a case report

BackgroundLiver injury related to Graves’ Disease (GD) includes hepatotoxicity of thyroid hormone excess, drug-induced liver injury, and changes resulting from concomitant liver disease. Methimazole (MMI) has been shown to induce several patterns of liver injury. However, the diagnosis and treatment of autoimmune hepatitis (AIH) overlapping with either GD or chronic hepatitis B are challenging.Case presentationA 35-year-old man from China presented with a two-year history of GD and a 10-day history of progressive jaundice. He had taken MMI for two months and discontinuing treatment due to liver toxicity 1 year ago and for another 6 days 20 days prior to hospitalization. The patient was diagnosed with GD overlapping with chronic hepatitis B and MMI-induced liver injury with early stage of acute-on-chronic liver failure on admission. However, the elevated aminotransferase and bilirubin levels could not be controlled after correction of liver failure and effective control of HBV replication and hyperthyroidism by daily oral entecavir and one-time oral administration of 131-iodine. The patient underwent liver biopsy on the 43rd day of hospitalization, showing HBsAg expression on the membrane of hepatocytes and typical histopathological characteristics of AIH. He was finally diagnosed with GD overlapping with chronic hepatitis B and MMI-induced liver injury and AIH. The elevated aminotransferase and bilirubin completely returned to normal by 3-month glucocorticoid therapy and continuous entecavir treatment and there was no recurrence during a 6-month follow-up, suggesting that AIH in this patient is different from classical AIH or GD-associated AIH.ConclusionsGD together with AIH is a complex and difficult subject. It needs to be clarified whether MMI or HBV can act as a trigger for AIH in this patient.

Chinese medicine in the treatment of autoimmune hepatitis: Progress and future opportunities.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease occurring in individuals of all ages with a higher incidence in females and characterized by hypergammaglobulinemia, elevated serum autoantibodies and histological features of interface hepatitis. AIH pathogenesis remains obscure and still needs in‐depth study, which is likely associated with genetic susceptibility and the loss of immune homeostasis. Steroids alone and in combination with other immunosuppressant agents are the primary choices of AIH treatment in the clinic, whereas, in some cases, severe adverse effects and disease relapse may occur. Chinese medicine used for the treatment of AIH has proven its merits over many years and is well tolerated. To better understand the pathogenesis of AIH and to evaluate the efficacy of novel therapies, several animal models have been generated to recapitulate the immune microenvironment of patients with AIH. In the current review, we summarize recent advances in the study of animal models for AIH and their application in pharmacological research of Chinese medicine‐based therapies and also discuss current limitations. This review aims to provide novel insights into the discovery of Chinese medicine‐originated therapies for AIH using cutting‐edge animal models.

Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis

BackgroundMost patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. AimTo evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. MethodsRetrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. ResultsOverall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. ConclusionsPatients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment.

Outcome of liver transplantation for autoimmune hepatitis in South Africa

Background: Liver Transplantation (LT) is the definitive treatment for Autoimmune Hepatitis (AIH) in patients with decompensated cirrhosis, liver failure and hepatocellular carcinoma. Outcomes of LT in AIH among black-Africans are not well-defined. We performed a single-center retrospective-review of adult LT patients. The study period was from 1st August 2004-31st August 2019. The primary aim was to document 1- & 5- year patient and graft survival. A secondary aim was to compare the survival of black-Africans to Caucasians. Data was analyzed using survival-analysis. Results: A total of 56 LT were performed for AIH. Sixty-seven percent (n = 38/56) had confirmed AIH on explant histology. Of these, the majority i.e., 79% (30/38) were female and 21% (8/38) were male. There were equal numbers of black-African 42% (n = 16/38) and Caucasian 42% (n = 16/38) patients. Rejection was four-times higher in black-Africans as compared to Caucasians. Forty-four percent (n = 17/38) had an acute rejection episode and 13% (5/38) had chronic rejection. Recurrence was found in four black-African females. Post-LT patient survival at 1- and 5- years was 86.5% and 80.7%, and graft survival was 94% and 70.8% respectively. The 5- year patient survival was insignificantly lower for black-Africans (73.9%) as compared to Caucasians (83.7%) (p - value 0.26, CI 6.3 - 12.2). Five-year graft survival was significantly lower among black-Africans (55%) as compared to Caucasians (84.8%) (p - value 0.003 CI 3.8 - 8.1) Conclusion: Black-Africans had a four-fold higher rate of rejection compared to Caucasians. Recurrent AIH was only found in patients of black ethnicity. Similar 1- & 5- year patient survival rates were observed between the two ethnicities. The 5-year graft survival among black-Africans was significantly lower than Caucasians.

RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism.

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.

Guidelines on the diagnosis and management of autoimmune hepatitis (2021)

Autoimmune hepatitis (AIH) is characterized by elevated serum aminotransferase and immunoglobulin G levels, seropositive results for autoantibodies and moderate to severe interface hepatitis in histologic findings. It will be most helpful in improving survival and life quality, if patients are diagnosed in the early stage and treated appropriately, which also helps relieve social medical burdens. Chinese consensus on the diagnosis and management of autoimmune hepatitis (2015) has contributed to standardizing the diagnosis and treatment of AIH. On the basis of the first consensus, at the end of 2021, under the organization of Chinese Society of Hepatology, experts devise this guide with latest advances aiming to further improve the level of diagnosis and management of autoimmune hepatitis.

Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis's mice through regulation of HDAC3

A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1β, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.

Autoimmune hepatitis in genetic syndromes: A literature review.

Genetic syndromes represent relevant and rare diseases. These conditions include a large amount of epidemiological, pathogenetic and clinical features. However, a systematic approach to genetic syndromes is often prevented by the rareness of these diseases. So, although clinical features are usually precisely defined, nowadays more uncommon associations between genetic syndromes and internal medicine related diseases have been insufficiently studied. Autoimmune hepatitis (AIH) is a chronic liver disease caused by loss of tolerance to hepatocyte-specific auto-antigens. Conversely, a better knowledge about specific genetic syndromes in which AIH is more frequent could be important in the clinical management of patients, both for an early diagnosis and for a prompt therapy. Furthermore, a systematic approach could explain if onset, clinical course, and response to treatment of AIH are typical for specific genetic syndromes. We took in consideration all the scientific articles reported in PubMed in the last 10 years, from 2010 to 2020. The purpose of this review is to explore the prevalence of AIH in genetic syndrome, but also to suggest new classification, that could be useful for pathogenetic hypothesis and clinical approach to genetic syndrome. From the 139 publications selected using keywords “autoimmune hepatitis” and “genetic syndrome”, 30 papers (21.6%) respected the chosen inclusion criteria, reporting the association between AIH in patients with a genetic syndrome. We have collected in all 47 patients with AIH and genetic syndrome, and with median age of 12.6-year-old. We suggest that when a patient presents a clinical picture of cryptogenic chronic hepatitis, that is unexplained, it is useful to explore differential diagnosis of AIH associated with genetic syndrome. Given the clinical relevance of this topic, further reports are needed to demonstrate our hypothesis and collect new evidence in this field.

One liver, two samples and two diagnoses-An example of how multiple samples by laparoscopically guided liver biopsy can be decisive.

Laparoscopically-guided liver biopsy was performed to make the diagnosis in a 54-year old female patient with clinical and serological signs of both non-alcoholic fatty liver disease and autoimmune hepatitis (AIH). Figure A shows a sample from the right liver lobe (HE, 20x) with a blue-boxed area (Figure B) (HE, 100x) demonstrating a total of eight portal tracts. Macrovesicular steatosis of about 50% of hepatocytes and mild lymphocyte infiltration were detected.

DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER TRANSPLANTATION IN CHILDREN. REVIEW

De novo autoimmune hepatitis (AIH) is a clinical disease similar to AIH that develops in liver transplant recipients with diseases other than AIH. Timely recognition of this disease makes it possible to avoid graft rejection and liver re-transplantation (LT), liver fibrosis, and can ensure a long life expectancy, given the effectiveness of more active immunosuppression with the use of corticosteroids and azathioprine, as in the treatment of idiopathic AIH. The de novo prefix was added to distinguish this condition from primary autoimmune hepatitis prior to transplant, but the diagnostic algorithm adopted generally accepted diagnostic criteria for autoimmune hepatitis. In fact, de novo autoimmune hepatitis is characterized by typical necroinflammation of the liver, rich in plasma cells, increased serum gammaglobulin levels, and the appearance of inorganic specific autoantibodies. However, the general signs of autoimmune hepatitis de novo, apparently, cannot be associated with an unambiguous pathophysiological pathway, since they can develop in patients undergoing liver transplantation due to different etiologies. The literature review presents such aspects as the prevalence of this case, the influence of the HLA phenotype on the manifestation and outcome of the disease, diagnosis and treatment. Objective. To conduct a literary meta-analysis of scientific publications on the development of De novo Autoimmune hepatitis after liver transplantation in children. Materials and methods. The authors selected scientific bases for the search such as: Web of science, Cyberleninka, UpToDate, Pubmed and Cochrane, Google Scholar. Results. A meta-analysis of scientific articles in English and Russian was carried out for the selected keywords. The causes of development were not infectious or surgical complications. Liver biopsy revealed histological changes typical of acute or chronic ovulation. High levels of transaminases, hypergammaglobulinemia, positivity to autoantibodies – ANA, AMA, SMA, anti-LKM-1. De novo AIH patients did not respond to conventional anti-rejection therapy, but responded only to classical AIH therapy.

S2616 Here’s the Tea — A Case of Drug-Induced Autoimmune Hepatitis and Salvage Therapy With Plasmapheresis

Introduction: Drug-induced liver injury (DILI) is a staple in the differential for acute hepatitis, though discerning agents as potentiating underlying autoimmune hepatitis (AIH) is challenging. Here, we present an unusual case of drug-induced AIH. Case Description/Methods: A 64 year old male with history of hypertension, tobacco use, and remote heavy alcohol use presented with 5 days of progressive jaundice, fatigue, acholic stools, and dark urine after consuming herbal teas made from fermented prickly pear as well as jujube/chili mix. Notable labs include AST 1677, ALT 1669, AP 196, T. Bili 16.8, and Globulin 3.9. Besides elevated IgG and IgA, chronic liver disease workup was negative. Biopsy finalized as moderate to severe plasma rich portal and lobular hepatitis with portal fibrosis. Patient was treated with Prednisone for seronegative drug-induced AIH with decline in transaminases. Interestingly, he had a monoclonal gammopathy on SPEP, which was unexpected given polyclonal hypergammaglobulinemia is typically seen with AIH. Immunofixation electrophoresis revealed elevated kappa/lambda ratio with negative bone survey and bone marrow biopsy leading to MGUS diagnosis. Three months later, he was readmitted with similar complaints and worsened liver dysfunction. Prednisone had been rapidly tapered within days of discharge due to PCP concerns, yet the patient had demonstrated improvement in transaminases until reengaging in moringa, ginseng, and turmeric herbal teas. Biopsy revealed progression to severe portal and lobular hepatitis with numerous plasma cells and stage 3/4 patchy bridging fibrosis. Serologies were now positive for AMA and ASMA, both 1:160. Patient was started on Methylprednisolone and Azathioprine, given normal TPMT, with labs essentially unchanged for 1 week. He then underwent a 5 day course of plasmapheresis (PLEX) as salvage therapy with downtrend in transaminases before discharge with Prednisone, Azathioprine, Tacrolimus, and Ursodiol. Discussion: Phenotypically, AIH and DILI are challenging to differentiate. Also difficult to determine is when drugs contribute to or reveal an underlying AIH, as we suspect occurred here. Drug-induced AIH has high relapse frequency post-corticosteroid withdrawal, especially when rechallenged, and this patient was given strict instructions not to consume herbal teas given concerns for disease progression. While PLEX is not a standard treatment for AIH, there are some studies indicating benefit, as seen with our patient who has been doing well since discharge.

O-24 A CASE SERIES OF CHLOROQUINE MONOTHERAPY TO INDUCE BIOCHEMICAL REMISSION IN PATIENTS WITH RELAPSED AUTOIMMUNE HEPATITIS

Azathioprine (AZA) and prednisone (PD) are the standard treatment (ST) for the onset or relapse of autoimmune hepatitis (AIH). Antimalarials were effective for maintenance of remission of AIH after immunosuppression withdrawal. Our aim is to describe a series of patients who relapsed after antimalarial withdrawal and achieved biochemical remission after reintroduction of chloroquine in monotherapy. Eight patients received chloroquine diphosphate (DCQ) 250mg/d or hydroxichloroquine (HCQ) 400-800mg/d in monotherapy for biochemical remission after relapse. The schedule is described below: histological remission (HR) with ST → ST withdrawal and antimalarial use for maintenance of remission for 1-3y → antimalarial withdrawal → relapse of AIH → reintroduction of antimalarial instead of ST, at the request of patient due to corticosteroids side effects (SE). Four out of 8 patients underwent liver biopsy to evaluate HR after at least 18mo of biochemical remission. Mean age at diagnosis of AIH of 36.2 ± 20.4y; 6 type-1, 2 anti-SLA/LP (5 reactive in 7 tested); 3 with cirrhosis at diagnosis. Mean doses of AZA/PD at HR were, respectively, 84.4 ± 18.6 and 9.4 ± 2.2mg/d. Mean interval between antimalarial withdrawal and relapse was 20.5 ± 34.1mo. Mean ALT at relapse was 139.7 ± 54.2 U/L. Three patients received DCQ and 5 HCQ. During HCQ intake 1 patient needed further adjustment of drug to 800 mg/d for 15 days due to worsening of ALT from 130 to 246 U/L, with subsequent reduction to the initial dose. Seven patients achieved biochemical remission, in a mean time of 14.2 ± 19.9mo; 3/4 had histological remission. The drug was well tolerated and there were no serious SE. CQ monotherapy was safe and effective for induction of remission in this subgroup of AIH. This finding raises arguments to include this drug as an option for treatment of AIH, not necessarily in monotherapy.

Glucose Metabolism Reprogramming of Regulatory T Cells in Concanavalin A-Induced Hepatitis.

Autoimmune hepatitis (AIH) is an inflammatory liver disease caused by a dysregulated immune response. Although the pathogenesis of AIH remains unclear, impaired regulatory T cells (Tregs) have been considered a driver of AIH development. Unlike autoreactive T cells, Tregs mainly utilize oxidative phosphorylation (OXPHOS) as their energy supply. Elevated glycolysis has been reported to limit the suppressive functions of Tregs. However, whether glucose metabolism reprogramming in Tregs is involved in AIH etiology remains unknown. The aim of this study was to examine alternations in Treg numbers and functions in AIH patients and concanavalin A (Con A)-induced hepatitis, while exploring associations between impaired Tregs and glucose metabolism. The frequency of Tregs was decreased in the peripheral blood but increased in liver biopsies of AIH patients. Moreover, immunosuppressive therapy rescued circulating Tregs in AIH. In Con A-induced immune hepatitis, enhanced intrahepatic Treg accumulation was observed over time, accompanied by reduced splenic Treg numbers. To investigate whether functional impairment of Tregs occurs in AIH, Tregs were isolated from experimental AIH (EAH) model mice and normal controls and the former displayed downregulated mRNA levels of FOXP3, CTLA4, CD103, TIGIT, CD39, and CD73. EAH model-derived Tregs also produced fewer anti-inflammatory mediators (TGF-β and IL-35) than control Tregs. Moreover, enhanced glycolysis and reduced OXPHOS were found in Tregs from EAH model mice, as reflected by elevated levels of key glycolytic enzymes (HK2, PK-M2, and LDH-A) and a decreased ATP concentration. This study revealed a decreased peripheral Treg frequency and abnormal intrahepatic Treg infiltration in AIH. It is first reported that glucose metabolism reprogramming is associated with decreases and functional impairments in the Treg population, promoting AIH development. Targeting glucose metabolism may provide novel insights for the treatment of AIH.

Daidzein ameliorated concanavalin A-induced liver injury through the Akt/GSK-3β/Nrf2 pathway in mice.

BackgroundDaidzein is a soybean isoflavone that has been shown in previous studies to have anti-inflammatory and antioxidant effects. However, it remains unknown whether daidzein plays a protective role against concanavalin A (Con A)-induced autoimmune hepatitis (AIH).MethodsIn this study, an animal model of AIH was constructed by intravenous injection of Con A (15 mg/kg). Daidzein (200 mg/kg/d) was intraperitoneally administered to mice for 3 days before the Con A injection. Alpha mouse liver 12 (AML-12) cells were incubated in the absence or presence of daidzein to determine whether daidzein can alleviate Con A-induced hepatotoxicity.ResultsThe findings showed that pretreatment with daidzein significantly reduced Con A-induced oxidative stress and hepatocyte apoptosis in Con A-induced liver injury. Pretreatment with daidzein significantly prevented the decrease of intrahepatic protein levels of phosphorylated Akt (p-Akt), phosphorylated GSK3β (p-GSK3β), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NOQ1 (NAD(P)H quinone dehydrogenase 1) in response to Con A administration. Meanwhile, malondialdehyde (MDA) production was reduced, and glutathione peroxidase (GPX), superoxide dismutase (SOD) activity, and SOD2 mRNA expression were elevated in daidzein-pretreated livers. In in vitro experiments, daidzein pretreatment prevented Con A-induced murine hepatocyte death. This effect was partly diminished by an inhibitor of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.ConclusionsThese results indicate that daidzein pretreatment attenuates Con A-induced liver injury through the Akt/GSK3β/Nrf2 pathway. Our findings provide new insights into the use of plant-derived products for AIH treatment beyond immunosuppression.

Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration.

Background: Autoimmune hepatitis (AIH) is a chronic autoimmune inflammatory disease that usually requires lifelong immunosuppression. Frequent recurrences after the discontinuation of therapy indicate that intrahepatic immune regulation is not restored by current treatments. Studies of other autoimmune diseases suggest that temporary depletion of B cells can improve disease progression in the long term. Methods: We tested a single administration of anti-CD20 antibodies to reduce B cells and the amount of IgG to induce intrahepatic immune tolerance. We used our experimental murine AIH (emAIH) model and treated the mice with anti-CD20 during the late stage of the disease. Results: After treatment, the mice showed the expected reductions in B cells and serum IgGs, but no improvements in pathology. However, all treated animals showed a highly altered serum protein expression pattern, which was a balance between inflammation and regeneration. Conclusions: In conclusion, anti-CD20 therapy did not produce clinically measurable results because it triggered inflammation, as well as regeneration, at the proteomic level. This finding suggests that anti-CD20 is ineffective as a sole treatment for AIH or emAIH.

PK/PD Modeling of the PDE7 Inhibitor-GRMS-55 in a Mouse Model of Autoimmune Hepatitis.

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

Formononetin protects against concanavalin-A-induced autoimmune hepatitis in mice through its anti-apoptotic and anti-inflammatory properties.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that seriously threatens the health of humans globally. Formononetin (FMN) is a natural herb extract with multiple biological functions. In this study, an experimental model of AIH was established in mice through the use of concanavalin A (ConA). To investigate the effects of FMN on ConA-induced hepatitis, the mice were pretreated with 50 or 100 mg/kg body mass of FMN. The results show that FMN alleviated ConA-induced liver injury of mice in a dose-dependent manner. Moreover, pretreatment with FMN inhibited the apoptosis of hepatocytes in the ConA-treated mice through downregulating the expression of pro-apoptotic proteins (Bax, cleaved caspase 9, and cleaved caspase 3) and upregulating the expression of anti-apoptotic protein (Bcl-2). It was also found that the levels of proinflammatory cytokines were greatly reduced in the serum and liver tissues of mice pretreated with FMN. Further studies showed that FMN reduced the level of phosphorylated nuclear factor kappa B (p-NF-κB) p65 and enhanced the level of IκBα (inhibitor of NF-κB), suggesting that FMN inhibits the activation of the NF-κB signaling pathway. In addition, FMN inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Therefore, FMN could be a promising agent for the treatment of AIH.

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis.

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.

Integrated bioinformatic analysis revealed biological processes and immune cells implicated in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease for which the pathogenesis remains incompletely understood. The current study aimed to reveal key biological processes and immune cells implicated in AIH by integrated bioinformatic analysis. The global gene expression in livers from wild-type BALB/c mice, mice with Tgfb1 deficiency, and mice with both Tgfb1 and Ifng deficiency was assessed by microarray data analysis. Differentially expressed genes were identified and subjected to functional enrichment analysis. AIH mice with Tgfb1 deletion showed significantly enhanced immune responses but impaired metabolic processes, whereas increased T cell activation and cytokine production, but weakened organic acid and lipid metabolic processes were observed in mice with deletion of both Tgfb1 and Ifng. In addition, infiltration of immune cells was evaluated by CIBERSORT. Increased infiltration of T cells, macrophages, and natural killer cells, and decreased infiltration of neutrophils, eosinophils, plasma cells, and B cells were observed in AIH mice. In conclusion, we identified potential biological processes and immune cells that contributed to AIH; further investigations are needed to confirm these findings and thus provide a potential novel therapeutic target for AIH treatment.

Laparoscopic hepatectomy for hepatic angiomyolipoma with preoperative diagnosis of other malignancy: a report of 2 cases

BackgroundHepatic angiomyolipoma (HAML) is a rare liver tumor, and hepatectomy is the only effective treatment. Due to the difficulty of correct diagnosis of HAML before surgery by image studies, more than 36.6% of reported HAMLs are misdiagnosed as other malignant liver tumors before surgery. As there are only few reported cases in which HAMLs were removed using laparoscopic hepatectomy, the effectiveness of laparoscopic hepatectomy for such HAMLs in which are diagnosed as other malignant liver tumor before surgery has not been reported.Case presentationCase 1: a 58-year-old female with a history of treatment for autoimmune hepatitis was preoperatively diagnosed with hepatocellular carcinoma (size: 20 mm) in segment 7 (S7) of the liver. The tumor was removed by laparoscopic partial resection and was diagnosed as a HAML through a pathological examination. The patient’s postoperative course was good, and she was recurrence-free at 37 months after the hepatectomy. Case 2: a 29-year-old female with a history of surgery for a right mature cystic teratoma was referred to our department to receive treatment for a growing 20-mm liver tumor with some calcification, which arose in S3 of the liver. A metastatic liver tumor derived from the mature cystic teratoma was suspected, and laparoscopic left lateral sectionectomy was performed. The liver tumor was diagnosed as a HAML after a pathological examination. The patient’s postoperative course was unremarkable, and more than 54 months have passed since the hepatectomy without any recurrence.ConclusionsTwo cases in which HAMLs were preoperatively diagnosed as other malignant liver tumor were successfully removed by laparoscopic hepatectomy with a correct postoperative diagnosis. Laparoscopic hepatectomy for the present 2 cases of HAML seemed to be effective for providing a correct diagnosis after the curative removement of liver tumor with a smaller invasion compared to open hepatectomy, and for denying risk of dissemination of the malignant tumor by needle biopsy that had to be considered before ruling out malignant tumor.