Management of autoimmune hepatitis induced by hepatitis delta virus

Approximately 12-72 million people worldwide are co-infected with hepatitis B virus(HBV)and hepatitis delta virus(HDV).This concurrent infection can lead to several severe outcomes with hepatic disease,such as cirrhosis,fulminant hepatitis,and hepatocellular carcinoma,being the most common.Over the past few decades,a correlation between viral hepatitis and autoimmune diseases has been reported.Furthermore,autoantibodies have been detected in the serum of patients co-infected with HBV/HDV,and autoimmune features have been reported.However,to date,very few cases of clinically significant autoimmune hepatitis(AIH)have been reported in patients with HDV infection,mainly in those who have received treatment with pegylated interferon.Interestingly,there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants.Consequently,several questions remain unanswered with the challenge to distinguish whether it is autoimmune or“autoimmune-like”hepatitis being the most crucial.Second,it remains uncertain whether autoimmunity is induced by HBV or delta virus.Finally,we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon.These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV,such as Bulevirtide or immu-nosuppressive drugs,are more appropriate for the management of patients with HDV and AIH.

Knockout of C6orf120 in Rats Alleviates Concanavalin A-induced Autoimmune Hepatitis by Regulating Macrophage Polarization

Objective The effect of the functionally unknown gene C6orf120 on autoimmune hepatitis was investigated on C6orf120 knockout rats(C6orf120^(-/-))and THP-1 cells.Method Six–eight-week-old C6orf120^(-/-)and wild-type(WT)SD rats were injected with Con A(16 mg/kg),and euthanized after 24 h.The sera,livers,and spleens were collected.THP-1 cells and the recombinant protein(rC6ORF120)were used to explore the mechanism in vitro.The frequency of M1 and M2 macrophages was analyzed using flow cytometry.Western blotting and PCR were used to detect macrophage polarization-associated factors.Results C6orf120 knockout attenuated Con A-induced autoimmune hepatitis.Flow cytometry indicated that the proportion of CD68^(+)CD86^(+)M1 macrophages from the liver and spleen in the C6orf120^(-/-)rats decreased.C6orf120 knockout induced downregulation of CD86 protein and the mRNA levels of related inflammatory factors TNF-α,IL-1β,and IL-6 in the liver.C6orf120 knockout did not affect the polarization of THP-1 cells.However,rC6ORF120 promoted the THP-1 cells toward CD68^(+)CD80^(+)M1 macrophages and inhibited the CD68^(+)CD206^(+)M2 phenotype.Conclusion C6orf120 knockout alleviates Con A-induced autoimmune hepatitis by inhibiting macrophage polarization toward M1 macrophages and reducing the expression of related inflammatory factors in C6orf120^(-/-)rats.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases:A case report

BACKGROUND Autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC)are two common clinical autoimmune liver diseases,and some patients have both diseases;this feature is called AIH-PBC overlap syndrome.Autoimmune thyroid disease(AITD)is the most frequently overlapping extrahepatic autoimmune disease.Immunoglobulin(IgG)4-related disease is an autoimmune disease recognized in recent years,characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues.CASE SUMMARY A 68-year-old female patient was admitted with a history of right upper quadrant pain,anorexia,and jaundice on physical examination.Laboratory examination revealed elevated liver enzymes,multiple positive autoantibodies associated with liver and thyroid disease,and imaging and biopsy suggestive of pancreatitis,hepatitis,and PBC.A diagnosis was made of a rare and complex overlap syndrome of AIH,PBC,AITD,and IgG4-related disease.Laboratory features improved on treatment with ursodeoxycholic acid,methylprednisolone,and azathioprine.CONCLUSION This case highlights the importance of screening patients with autoimmune diseases for related conditions.

Fermented Lentinus edodes extract containingα-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Autoimmune hepatitis(AIH)is a chronic inflammatory liver disease that threatens human health worldwide.The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containingα-glucan(FLA),in a concanavalin A(Con A)-induced AIH mouse model and to determine the underlying liver-protective mechanism.The results showed that compared with the model group,the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased,and the degree of inflammatory cell infiltration in liver,thymus and spleen was significantly reduced.Quantitative polymerase chain reaction,immunohistochemistry,and Western blotting showed that FLA pre-treatment inhibited the Con A-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2.Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway.Thus,FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes.Up-regulation of NRF2 signaling pathway,down-regulation of TRAF6/NF-κB signaling pathway,and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

Autoimmune hepatitis and primary sclerosing cholangitis after direct-acting antiviral treatment for hepatitis C virus:A case report

BACKGROUND Chronic hepatitis C virus(HCV)infection is a major global health concern that leads to liver fibrosis,cirrhosis,and cancer.Regimens containing direct-acting antivirals(DAAs)have become the mainstay of HCV treatment,achieving a high sustained virological response(SVR)with minimal adverse events.CASE SUMMARY A 74-year-old woman with chronic HCV infection was treated with the DAAs ledipasvir,and sofosbuvir for 12 wk and achieved SVR.Twenty-four weeks after treatment completion,the liver enzyme and serum IgG levels increased,and antinuclear antibody became positive without HCV viremia,suggesting the development of autoimmune hepatitis(AIH).After liver biopsy indicated AIH,a definite AIH diagnosis was made and prednisolone was initiated.The treatment was effective,and the liver enzyme and serum IgG levels normalized.However,multiple strictures of the intrahepatic and extrahepatic bile ducts with dilatation of the peripheral bile ducts appeared on magnetic resonance cholangiopancreatography after 3 years of achieving SVR,which were consistent with primary sclerosing cholangitis.CONCLUSION The potential risk of developing autoimmune liver diseases after DAA treatment should be considered.

Advancements in autoimmune hepatitis management:Perspectives for future guidelines

The first-line treatment for autoimmune hepatitis involves the use of prednisone or prednisolone either as monotherapy or in combination with azathioprine(AZA).Budesonide has shown promise in inducing a complete biochemical response(CBR)with fewer adverse effects and is considered an optional first-line treatment,particularly for patients without cirrhosis;however,it is worth noting that the design of that study favored budesonide.A recent real-life study revealed higher CBR rates with prednisone when equivalent initial doses were administered.Current guidelines recommend mycophenolate mofetil(MMF)for patients who are intolerant to AZA.It is important to mention that the evidence supporting this recommendation is weak,primarily consisting of case series.Nevertheless,MMF has demonstrated superiority to AZA in the context of renal transplant.Recent comparative studies have shown higher CBR rates,lower therapeutic failure rates,and reduced intolerance in the MMF group.These findings may influence future guidelines,potentially leading to a significant modification in the first-line treatment of autoimmune hepatitis.Until recently,the only alternative to corticosteroids was lifelong maintenance treatment with AZA,which comes with notable risks,such as skin cancer and lymphoma.Prospective trials are essential for a more comprehensive assessment of treatment suspension strategies,whether relying on histological criteria,strict biochemical criteria,or a combination of both.Single-center studies using chloroquine diphosphate have shown promising results in significantly reducing relapse rates compared to placebo.However,these interesting findings have yet to be replicated by other research groups.Additionally,second-line drugs,such as tacrolimus,rituximab,and infliximab,should be subjected to controlled trials for further evaluation.

Immunological crossroads:The intriguing dance between hepatitis C and autoimmune hepatitis

Delving into the immunological crossroads of liver diseases,this editorial explores the dynamic interplay between hepatitis C virus(HCV)and autoimmune hepatitis(AIH).While HCV primarily manifests as a viral infection impacting the liver,previous studies unveil a captivating connection between HCV and the emergence of AIH.The dance of the immune system in response to HCV appears to set the stage for an intriguing phenomenon-an aberrant autoimmune response leading to the onset of AIH.Evidence suggests a heightened presence of autoimmune markers in individuals with chronic HCV infection,hinting at a potential overlap between viral and autoimmune liver diseases.Navigating the intricate terrain of viral replication,immune response dynamics,and genetic predisposition,this editorial adds a layer of complexity to our understanding of the relationship between HCV and AIH.In this immunological crossroads,we aim to unearth insights into the complex interplay,using a compelling case where AIH and primary sclerosing cholangitis overlapped following HCV treatment with direct-acting antivirals as background.

Research progress on the mechanism of traditional Chinese medicine in the treatment of autoimmune hepatitis

Autoimmune hepatitis is an inflammatory liver disease primarily mediated by T cell.It has not been fully elucidated about the pathogenesis,and it is presently thought to be related to genetic susceptibility,infection and environmental triggers,and abnormal autoimmune regulation.Recent studies have found that traditional Chinese medicine can improve the biochemical indicators and clinical symptoms of patients with autoimmune hepatitis.This article reviews the specific mechanism of traditional Chinese medicine on treating autoimmune hepatitis in order to propose new ideas for its clinical diagnosis and treatment.

Drug induced autoimmune hepatitis:An unfortunate case of herbal toxicity from Skullcap supplement:A case report

BACKGROUND The surge in traditional herbal dietary supplement(HDS)popularity has led to increased drug-induced liver injuries(DILI).Despite lacking evidence of efficacy and being prohibited from making medical claims,their acceptance has risen over sevenfold in the last two decades,with roughly 25%of United States(US)adults using these supplements monthly.An estimated 23000 emergency room visits annually in the US are linked to HDS side effects.NIH-funded research suggests HDS contribute to 7-20%of DILI cases,with similar trends in Europe—Spain reporting 2%and Iceland up to 16%.Patients with acute liver failure from HDS undergo liver transplantation more frequently than those from prescription medicines.Here we describe a case of drug-induced autoimmune hepatitis due to Skullcap supplements,this association appears to be the first documented instance in literature.CASE SUMMARY A middle-aged Caucasian woman,previously healthy,presented with sudden jaundice.Four months earlier,her liver enzymes were normal.She mentioned recent use of Skullcap mushroom supplements.Tests for chronic liver disease were negative.The first liver biopsy indicated severe resolving drug-induced liver injury.Despite treatment,she was readmitted due to worsening jaundice.Followup tests raised concerns about autoimmune hepatitis.A subsequent biopsy confirmed this diagnosis.The patient responded as expected to stopping the medication with improvement in liver enzymes.CONCLUSION This scenario highlights an uncommon instance of DILI caused by Skullcap supplements.It's crucial for hepatologists to recognize this connection due to the increasing prevalence of herbal supplements.

Isolated IgG4-associated autoimmune hepatitis or the first manifestation of IgG4-related disease?

To the Editor:Immunoglobulin G4(IgG4)-associated autoimmune hepatitis(IgG4-AIH)is a novel and rare disease entity,characterized by sig-nificant infiltration of IgG4-expressing plasma cells in the liver.The classification of of IgG4-AIH as a subtype of AIH or an early manifestation of IgG4-related disease(IgG4-RD)remains controversial.Herein,we discuss an interesting clinical vignette of IgG4-AIH in a gentleman with no significant past medical history,who presented with undifferentiated symptoms and elevated aminotransferases.

Pien Tze Huang alleviates Concanavalin A-induced autoimmune hepatitis by regulating intestinal microbiota and memory regulatory T cells

BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.

Clinical characteristics and outcomes of COVID-19 in patients with autoimmune hepatitis:A population-based matched cohort study

BACKGROUND Patients with autoimmune hepatitis(AIH)require life-long immunosuppressive agents that may increase the risk of poor coronavirus disease 2019(COVID-19)outcomes.There is a paucity of large data at the population level to assess whether patients with AIH have an increased risk of severe diseases.AIM To evaluate the impact of pre-existing AIH on the clinical outcomes of patients with COVID-19.METHODS We conducted a population-based,multicenter,propensity score-matched cohort study with consecutive adult patients(≥18 years)diagnosed with COVID-19 using the TriNeTx research network platform.The outcomes of patients with AIH(main group)were compared to a propensity score-matched cohort of patients:(1)Without chronic liver disease(CLD);and(2)Patients with CLD except AIH(non-AIH CLD)control groups.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.The primary outcome was all-cause mortality,and secondary outcomes were hospitalization rate,need for critical care,severe disease,mechanical ventilation,and acute kidney injury(AKI).For each outcome,the risk ratio(RR)and confidence intervals(CI)were calculated to compare the association of AIH with the outcome.RESULTS We identified 375 patients with AIH,1647915 patients with non-CLD,and 15790 patients with non-AIH CLD with COVID-19 infection.Compared to non-CLD patients,the AIH cohort had an increased risk of all-cause mortality(RR=2.22;95%CI:1.07-4.61),hospitalization rate(RR=1.78;95%CI:1.17-2.69),and severe disease(RR=1.98;95%CI:1.19-3.26).The AIH cohort had a lower risk of hospitalization rate(RR=0.72;95%CI:0.56-0.92),critical care(RR=0.50;95%CI:0.32-0.79),and AKI(RR=0.56;95%CI:0.35-0.88)compared to the non-AIH CLD patients.CONCLUSION Patients with AIH are associated with increased hospitalization risk,severe disease,and all-cause mortality compared to patients without pre-existing CLD from the diagnosis of COVID-19.However,patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD.

Autoimmune hepatitis and eosinophilia:A rare case report

BACKGROUND Autoimmune hepatitis consists of a chronic liver disease whose etiology is unknown.It is comprised of relevant immunological aspects and of immunemediated liver injury.Eosinophilia may be a considerable feature,particularly happening in male patients.CASE SUMMARY We report here a Crohn´s disease patient presenting with de novo hypergammaglobulinemia,circulating autoantibodies and elevated transaminase levels.He also had significant peripheral eosinophilia and elevated immunoglobulin E levels at diagnosis.The pathology findings from liver biopsy were compatible with autoimmune hepatitis with eosinophilic infiltration.CONCLUSION This is the first report of autoimmune hepatitis with exuberant eosinophilic infiltration in the liver and bone marrow,described in a patient with Crohn’s disease.

Hepatitis: A Case of Infectious and Autoimmune Hepatitis Occurring with Neurosyphilis

The liver is an organ that withstands a lot of insults due to various things such as infection, toxins and even our own immune system. There are injuries to the liver that are relatively common in medicine such as viral hepatitis caused by different strains of Hepatitis A-E, autoimmune hepatitis, and injury by drugs such as acetaminophen. However, syphilis causing hepatitis is not seen often and there are certain features that distinguish syphilitic hepatitis that should be reported more to distinguish its characteristic features.

Seronegative autoimmune hepatitis in childhood

Comprehensive guidelines on seropositive autoimmune hepatitis have been published for both adults and children,although these guidelines comprise only limited knowledge about seronegative autoimmune hepatitis.Autoimmune hepatitis presents as an acute or chronic progressive disease and poor outcomes are inevitable if left untreated.The absence of autoantibody positivity,hypergammaglobulinemia and lack of comprehensive algorithms makes seronegative autoimmune hepatitis a mysterious disease.In general,seronegative autoimmune hepatitis often presents with acute hepatitis,and its treatment and prognosis similar to seropositive autoimmune hepatitis.The present review focuses on the known characteristics of seronegative autoimmune hepatitis in childhood,and those of which current knowledge is vague.

Reactivation of hepatitis B virus infection – an important aspect of multifaceted problem

In this editorial we comment on the article published in the recent issue of the W orld Journal of Gastroenterology.We focus specifically on the problem of occult hepatitis B virus(HBV)infection,that is a result of previous hepatitis B(PHB)and a source for reactivation of HBV.The prevalence of PHB is underestimated due to the lack of population testing programs.However,this condition not only com-plicate anticancer treatment,but may be responsible for the development of other diseases,like cancer or autoimmune disorders.Here we unveil possible mecha-nisms responsible for realization of these processes and suggest practical approa-ches for diagnosis and treatment.

Trends of autoimmune liver disease inpatient hospitalization and mortality from 2011 to 2017:A United States nationwide analysis

BACKGROUND Autoimmune liver diseases(AiLD)encompass a variety of disorders that target either the liver cells(autoimmune hepatitis,AIH)or the bile ducts[primary biliary cholangitis(PBC),and primary sclerosing cholangitis(PSC)].These conditions can progress to chronic liver disease(CLD),which is characterized by fibrosis,cirrhosis,and hepatocellular carcinoma.Recent studies have indicated a rise in hospitalizations and associated costs for CLD in the US,but information regarding inpatient admissions specifically for AiLD remains limited.AIM To examine the trends and mortality of inpatient hospitalization of AiLD from 2011 to 2017.METHODS This study is a retrospective analysis utilizing the National Inpatient Sample(NIS)databases.All subjects admitted between 2011 and 2017 with a diagnosis of AiLD(AIH,PBC,PSC)were identified using the International Classification of Diseases(ICD-9)and ICD-10 codes.primary AiLD admission was defined if the first admission code was one of the AiLD codes.secondary AiLD admission was defined as having the AiLD diagnosis anywhere in the admission diagnosis(25 diagnoses).Subjects aged 21 years and older were included.The national estimates of hospitalization were derived using sample weights provided by NIS.χ^(2)tests for categorical data were used.The primary trend characteristics were in-hospital mortality,hospital charges,and length of stay.RESULTS From 2011 to 2017,hospitalization rates witnessed a significant decline,dropping from 83263 admissions to 74850 admissions(P<0.05).The patients hospitalized were predominantly elderly(median 53%for age>65),mostly female(median 59%)(P<0.05),and primarily Caucasians(median 68%)(P<0.05).Medicare was the major insurance(median 56%),followed by private payer(median 27%)(P<0.05).The South was the top geographical distribution for these admissions(median 33%)(P<0.05),with most admissions taking place in big teaching institutions(median 63%)(P<0.05).Total charges for admissions rose from 66031 in 2011 to 78987 in 2017(P<0.05),while the inpatient mortality rate had a median of 4.9%(P<0.05),rising from 4.67%in 2011 to 5.43%in 2017.The median length of stay remained relatively stable,changing from 6.94 days(SD=0.07)in 2011 to 6.51 days(SD=0.06)in 2017(P<0.05).Acute renal failure emerged as the most common risk factor associated with an increased death rate,affecting nearly 68%of patients(P<0.05).CONCLUSION AiLD-inpatient hospitalization showed a decrease in overall trends over the studied years,however there is a significant increase in financial burden on healthcare with increasing in-hospital costs along with increase in mortality of hospitalized patient with AiLD.

Autoimmune hepatitis,one disease with many faces:Etiopathogenetic,clinico-laboratory and histological characteristics

Autoimmune hepatitis(AIH) is an unresolving progressive liver disease of unknown etiology characterized byhypergammaglobulinemia,autoantibodies detection and interface hepatitis.Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical,laboratory and histological features,AIH diagnosis may be potentially difficult.Therefore,in this in-depth review we summarize the substantial progress on etiopathogenesis,clinical,serological and histological phenotypes of AIH.AIH has a global distribution affecting any age,both sexes and all ethnic groups.Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis.Hypergammaglobulinemia with selective elevation of IgG is found in most cases.Autoimmune attack is perpetuated,possibly via molecular mimicry,and favored by the impaired control of T-regulatory cells.Histology(interface hepatitis,emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic,are still the hallmark for a timely diagnosis.AIH remains a major diagnostic challenge.AIH should be considered in every case in the absence of viral,metabolic,genetic and toxic etiology of chronic or acute hepatitis.Laboratory personnel,hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.

Autoimmune hepatitis and IgG4-related disease

IgG4-related disease(IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis(AIH), called IgG4-associated AIH(IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.

Autoimmune hepatitis: standard treatment and systematic review of alternative treatments

Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated,it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine,and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine,but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug,and has good efficacy particularly for patients intolerant to azathioprine,but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine,tacrolimus,everolimus and sirolimus are available. More recently,experience with the anti-tumour necrosis factoralpha infliximab and the anti-CD20 rituximab has been published,with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.