Hepatic inflammation and progressive liver fibrosis in chronic liver disease

Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory actions.Responses,however,are commonly incomplete and inconsistently achieved.The fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive therapies.Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes.Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species.Anti-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental therapies.Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.

Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora(dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens(molecular mimicry). Activated gutderived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis

To assess the value of magnetic resonance elastography(MRE) in detecting advanced fibrosis/cirrhosis in autoimmune hepatitis(AIH).METHODS In this retrospective study, 36 patients(19 treated and 17 untreated) with histologically confirmed AIH and liver biopsy performed within 3 mo of MRE were identified at a tertiary care referral center. Liver stiffness(LS) with MRE was calculated by a radiologist, and inflammation grade and fibrosis stage in liver biopsy was assessed by a pathologist in a blinded fashion. Two radiologistsevaluated morphological features of cirrhosis on conventional magnetic resonance imaging(MRI). Accuracy of MRE was compared to laboratory markers and MRI for detection of advanced fibrosis/cirrhosis.RESULTS Liver fibrosis stages of 0, 1, 2, 3 and 4 were present in 4, 6, 7, 6 and 13 patients respectively. There were no significant differences in distribution of fibrosis stage and inflammation grade between treated and untreated patient groups. LS with MRE demonstrated stronger correlation with liver fibrosis stage in comparison to laboratory markers for chronic liver disease(r = 0.88 vs-0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed(3.7 k Pa vs 3.84 k Pa) but was not statistically significant. MRE had an accuracy/sensitivity/specificity/positive predictive value/negative predictive value of 0.97/90%/100%/100%/90% and 0.98/92.3%/96%/92.3%/96% for detection of advanced fibrosis and cirrhosis, respectively. The performance of MRE was significantly better than laboratory tests for detection of advanced fibrosis(0.97 vs 0.53-0.80, P < 0.01), and cirrhosis(0.98 vs 0.58-0.80, P < 0.01) and better than conventional MRI for diagnosis of cirrhosis(0.98 vs 0.78, P = 0.002).CONCLUSION MRE is a promising modality for detection of advanced fibrosis and cirrhosis in patients with AIH with superior diagnostic accuracy compared to laboratory assessment and MRI.

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

BACKGROUND 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.

Difficult treatment decisions in autoimmune hepatitis

Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.

Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment

Non-classical manifestations of autoimmune hepatitis can delay diagnosis and treatment.Our aims were to describe the clinical phenotypes that can confound the diagnosis,detail scoring systems that can ensure their recognition,and outline advances in treatment that can improve their outcome.Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into personal libraries spanning 32 years.Acute severe or asymptomatic presentations and atypical histological findings,including centrilobular zone 3 necrosis and concurrent bile duct changes,are compatible with the diagnosis.Cholangiographic abnormalities may be present in children and adults with the disease,and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic features.Asymptomatic patients frequently become symptomatic;mild disease can progress;and there are no conf ident indices that justify withholding treatment.Two diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing features.Normal liver tests and tissue constitute the optimal end point of treatment,and the f irst relapse is an indication for long-term azathioprine therapy.Cyclosporine,tacrolimus and mycophenolate mofetil are promising salvage therapies,and budesonide with azathioprine may be a superior frontline treatment.We conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly,diagnosed accurately,and treated effectively.

Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

Mucosal-associated invariant T(MAIT)cells have been described in liver and nonliver diseases,and they have been ascribed antimicrobial,immune regulatory,protective,and pathogenic roles.The goals of this review are to describe their biological properties,indicate their involvement in chronic liver disease,and encourage investigations that clarify their actions and therapeutic implications.English abstracts were identified in PubMed by multiple search terms,and bibliographies were developed.MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines.Diverse pro-inflammatory,anti-inflammatory,and immune regulatory cytokines are released;infected cells are eliminated;and memory cells emerge.Circulating MAIT cells are hyper-activated,immune exhausted,dysfunctional,and depleted in chronic liver disease.This phenotype lacks disease-specificity,and it does not predict the biological effects.MAIT cells have presumed protective actions in chronic viral hepatitis,alcoholic hepatitis,non-alcoholic fatty liver disease,primary sclerosing cholangitis,and decompensated cirrhosis.They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis.Local factors in the hepatic microenvironment(cytokines,bile acids,gut-derived bacterial antigens,and metabolic by-products)may modulate their response in individual diseases.Investigational manipulations of function are warranted to establish an association with disease severity and outcome.In conclusion,MAIT cells constitute a disease-nonspecific,immune response to chronic liver inflammation and infection.Their pathological role has been deduced from their deficiencies during active liver disease,and future investigations must clarify this role,link it to outcome,and explore therapeutic interventions.