SUMMARY BackgroundAutoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AimTo review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. MethodsPublished studies on AIH extracted mainly from PubMed during the last 15 years. ResultsAutoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients -particularly children, elderly and acute cases -IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. ConclusionsAutoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.

ANA-H and/or SMA-AA does not exclude AIH, the characterAntibodies to nuclei (ANA), smooth muscle (SMA), and ization of ANA and SMA may help to discriminate between liver/kidney microsomes type 1 (anti-LKM1) may occur in the two conditions. As compared with the seronegative counchronic hepatitis C. Distinct subspecificities, including ANA terpart, autoantibody-positive chronic hepatitis C is more with the homogeneous pattern (ANA-H) and SMA with anticommon in females and exhibits a more severe biochemical actin specificity (SMA-AA), are found in autoimmune hepatiand histological activity. The response to IFN therapy, howtis (AIH). This study was performed to characterize the hepaever, is similar. (HEPATOLOGY 1997;26:561-566.) titis C virus (HCV)-associated autoantibodies and to evaluate their influence on the profile of the disease. Two hundred ninety consecutive patients with chronic hepatitis C and 35A variety of immunological abnormalities has been decontrol cases with AIH were screened for autoantibodies by scribed in patients with chronic hepatitis C. In particular, indirect immunofluorescence (IFL) at 1:40 serum dilution. the occurrence of serum non-organ-specific autoantibodies The ANA pattern was defined by IFL on HEp-2 cells and the has been extensively studied: smooth muscle (SMA) and anti-SMA-AA identified by the presence of at least two of the nuclear (ANA) antibodies have been detected in approxifollowing elements: 1) SMA T or SMA G pattern by IFL on mately one third of the cases, 1,2 while antibodies to liver/ kidney sections; 2) XR 1 precipitating system by counterimmu-kidney microsomes type 1 (anti-LKM1) have been found noelectrophoresis; or 3) typical pattern by IFL on liver sec-more rarely (from 0% to 5%). [2][3][4] Variations in the autoantitions from phalloidin-intoxicated rats. ANA, SMA, and anti-body prevalence among the reports so far published 1-7 have LKM1 occurred in 9%, 20%, and 6% of chronic hepatitis C been attributed both to different experimental conditions in cases, respectively. The overall prevalence of autoantibodies the immunofluorescence (IFL) procedure and to ethnical and was 30% (87 of 290). Compared with AIH, HCV-associated geographical differences in the study populations. ANA and SMA exhibited ANA-H and SMA-AA at a lower Most reports agree that the autoantibody positivity does prevalence (38% vs. 71%, P Å .04 and 8% vs. 87%, P õ not influence either the clinical and biochemical profile of .000001, respectively) and had a lower median titer (1:80 vs. chronic hepatitis C or the response to interferon (IFN) alfa. 1:320, P õ .001 and 1:40 vs. 1:320, P õ .000001, respec-Some data, however, have been published on the occurrence tively). The concomitant positivity for ANA-H and SMA-AA of disease activity exacerbations in patients with serum autowas detected in none of the HCV cases, but in 46% of AIH antibodies during IFN treatment. 8-10 sera (P õ .000001). Two parameters were independently asThe major impact of the above autoantibodies in the hepasociated with the autoantibodie...

Background-Several retrospective and prospective studies report an increased prevalence of non-organ-specific autoantibodies (NOSAs) in patients with hepatitis C virus (HCV) related chronic liver disease (CLD). Some of the data so far available are controversial and the true prevalence of NOSAs in the general population is still not known. Aim-To explore the prevalence of NOSAs, their relation to diVerent HCV genotypes, and the presence and severity of CLD in the general population of Northern Italy. Patients-All 226 anti-HCV positive and 87 hepatitis B surface antigen (HBsAg) positive patients of the Dionysos cohort study were analysed and compared with sex and age matched cases (226) negative for both anti-HCV antibody and HBsAg selected from the same cohort. Methods-Sera tested for the presence of NOSAs (anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomes type 1 antibody (LKM1)) were screened by indirect immunofluorescence at a 1:40 serum dilution. HCV RNA and HCV genotypes were also determined by nested polymerase chain reaction (PCR) of the 5' non-coding region and by PCR amplification of the core region with type specific primers. Results-The overall prevalence of NOSA reactivity was significantly higher in anti-HCV positive subjects than in both normal and pathological controls (25% v 6% and 7% respectively, p<0.05). ANA, SMA, and LKM1 occurred in 16, 10, and 1.3% of cases respectively. No specific association between NOSAs and a specific HCV genotype was found. NOSAs were found more often associated with more than one genotype (35.7%) and with untypable genotypes (34.6%), although the association was not statistically significant. NOSAs were associated with HCV RNA and CLD but not with the presence of cirrhosis and/or hepatocellular carcinoma. On univariate analysis, NOSA reactivity was independently associated with abnormal alanine aminotransferase (p<0.01) and -glutamyltranspeptidase levels (p<0.05). The risk for the presence of NOSAs was 5.1 times higher in anti-HCV subjects than in controls. Conclusions-In the general population the prevalence of NOSAs is higher in anti-HCV positive subjects than in normal or disease controls. Moreover NOSAs are associated with CLD and with a more active disease in terms of alanine aminotransferase activity. (Gut 1999;45:435-441)

Immunotolerance is maintained by regulatory T cells (Tregs), including CD4 1 CD25 hi , CD8 1 CD28 2 , cd, and CD3 1 CD56 1 [natural killer T (NKT)] cells. CD4 1 CD25 hi cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and functionrelated intracellular molecules in cd, CD8 1 CD28 2 , NKT, and CD4 1 CD25 hi cells. CD4 1 CD25 hi T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-c) production by CD4 1 CD25 2 target cells. Liver forkhead box P3-positive (FOXP3 1 ) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4 1 CD25 hi T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8 1 CD28 2 T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, cd T cells in AIH patients were more numerous versus healthy controls and had an inverted Vd1/Vd2 ratio and higher IFN-c and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3 1 cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and cd T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010;52:999-1007) A utoimmune hepatitis (AIH) is an immunemediated liver disease characterized by high levels of aminotransferases and gamma-globulins, circulating autoantibodies, and histological evidence of interface hepatitis. 1-3 Two AIH subsets are conventionally recognized according to their autoantibody profile 4 : type 1 AIH (AIH-1), which is characterized by positivity for anti-nuclear antibody (ANA) and/or

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Eighty-four consecutive subjects with nonalcoholic fatty liver disease (NAFLD) were tested for non-organ-specific autoantibodies (NOSA) by indirect immunoflorescence. Indices of insulin resistance and biochemical and anthropometric parameters were assessed. The overall prevalence of anti-nuclear-antibodies (ANA), smooth muscle antibodies (SMA) and anti-mitochondrial-antibodies (AMA) was 35.7% (30/84), 18 subjects (21.4%) being positive for ANA, 4 (4.7%) for SMA, 6 for ANA and SMA, and 2 for AMA. NOSA-positive subjects were older (P < 0.01) and mostly females (63.3%). No significant difference was found in the age-corrected parameters studied, except for copper and ceruloplasmin, which was more elevated in NOSA-positive patients. The subset of high titer (>1:100) ANA-positive patients had significantly (P < 0.05) greater insulin resistance than ANA-negative patients. In contrast, SMA-positive patients had higher gammaglobulin and significantly lower insulin resistance as compared to high-titer ANA-positive patients. In 3 NOSA-positive but not in NOSA-negative patients, liver biopsy disclosed features of overlapping NASH with autoimmune hepatitis, partially responding to diet combined with steroid treatment. In conclusion, NOSA positivity in NAFLD is more prevalent than in the general population. High-titre ANA but not SMA positivity is associated with insulin resistance.

Antinuclear antibodies reactivities are present in more than half of primary biliary cirrhosis patients and target diverse autoantigens located in distinct subnuclear structures. Anti-gp210 identifies a subgroup of primary biliary cirrhosis patients with more serious liver disease. Positivity for anti-Sp100, anti-gp210, and anti-lamin B receptor, either alone or in combination, may act as a serologic marker of antimitochondrial antibodies negative primary biliary cirrhosis.

The prevalence of the recently described deamidated gliadin peptide antibodies was compared with that of the routinely used antigliadin, antiendomysial, and tissue transglutaminase antibodies in the sera of 128 untreated celiac patients and 134 controls. Sensitivity and specificity for celiac disease were 83.6 and 90.3% for IgA and 84.4 and 98.5% for IgG antibodies to deamidated gliadin peptides. The new test displayed higher diagnostic accuracy than antigliadin antibodies and, although less sensitive than antiendomysial and tissue transglutaminase antibodies, showed significantly higher specificity than tissue transglutaminase antibodies (P < 0.001). Persistence of peptide antibodies after gluten withdrawal was an expression of low compliance with the diet and of the lack of improvement of the intestinal mucosa. The combined use of tissue transglutaminase and deamidated gliadin peptide antibodies seems to be a very useful tool for celiac disease diagnosis. Moreover, antibodies to deamidated gliadin peptides can be helpful in disease follow-up.