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Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease of unknown aetiology characterized by the presence of autoantibodies, hypergammaglobulinaemia with specific IgG increase and interface hepatitis on liver histology. The clinical course of AIH is classically characterized by fluctuating periods of decreased or increased disease activity and therefore its clinical spectrum is variable ranging from no symptoms to severe acute hepatitis and even fulminant hepatic failure. Acute presentation may not differ from acute hepatitis of other causes and diagnosis can be difficult. We describe our experience on diagnostic performance of the two AIH scoring systems in acute onset of AIH and found that revised version of the original criteria (1999) achieves the diagnosis in about 30% of patients who presented with normal IgG serum levels and lower frequency of autoantibody positivity in whom the simplified score did not allow the diagnosis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: The simplified criteria for the diagnosis of autoimmune hepatitis (AIH) include immunofluorescence testing (IFT) of antinuclear and smooth muscle autoantibodies (ANA and SMA) on rodent tissue sections. We aimed to establish scoring criteria for the implementation of ANA IFT on human epithelioma-2 (HEp-2) cells and ELISA-based testing., Methods: ANA and SMA reactivity of 61 AIH sera and 72 non-alcoholic fatty liver disease controls were separately assessed on tissue sections and HEp-2 cells to compare the diagnostic value at increasing titers. A total of 113 patients with AIH at diagnosis and 202 controls from 3 European centers were assessed by IFT as well as 3 different commercially available ANA ELISA and 1 anti-F-actin ELISA., Results: ANA assessment by IFT on liver sections had 83.6% sensitivity and 69.4% specificity for AIH at a titer of 1:40. On HEp-2 cells, sensitivity and specificity were 75.4% and 73.6%, respectively, at an adjusted titer of 1:160. Area under the curve (AUC) values of ANA ELISA ranged from 0.70-0.87, with ELISA coated with HEp-2 extracts in addition to selected antigens performing significantly better. SMA assessment by IFT had the highest specificity for the SMA-VG/T pattern and anti-microfilament reactivity on HEp-2 cells. ELISA-based anti-F-actin evaluation was a strong predictor of AIH (AUC 0.88) and performed better than SMA assessment by IFT (AUC 0.77-0.87)., Conclusion: At adjusted cut-offs, both ANA IFT using HEp-2 cells and ELISA-based autoantibody evaluation for ANA and SMA are potential alternatives to tissue-based IFT for the diagnosis of AIH., Lay Summary: Autoantibodies are a hallmark of autoimmune hepatitis and are traditionally tested for by immunofluorescence assays on rodent tissue sections. Herein, we demonstrate that human epithelioma cells can be used as a reliable substrate for immunofluorescence testing. ELISA-based testing is also a potentially reliable alternative for autoantibody assessment in autoimmune hepatitis. We propose the implementation of these testing methods into the simplified criteria for the diagnosis of autoimmune hepatitis., Competing Interests: Conflict of interest Weiler-Normann C reports speaker's fees from Euroimmun and Werfen (Inova) to her institution. All other authors declare no conflict of interest with respect to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: High frequency (130 Hz) subthalamic Deep-Brain-Stimulation (STN-DBS) optimally improves cardinal motor symptoms in Parkinson disease (PD). Low stimulation frequencies (60-80 Hz) improve axial symptoms in some patients and, according to preliminary evidences, may also have a beneficial effect on the cognitive component of motor planning., Objective: To analyze the configuration of the P300 component of cortical event-related auditory potentials (ERPs), a reliable index of attentive cognitive functions, at different stimulation frequencies in STN-DBS in PD patients., Methods: 12 PD patients underwent ERPs recordings using a standard oddball auditory paradigm with STN-DBS at 60 Hz, 80 Hz, 130 Hz, and OFF-stimulation, applied in a randomized double-blind sequence. ERPs analysis considered the peak amplitude and latency of the P300 components at midline electrode positions (Fz, Cz, Pz)., Results: P300 latency over Cz and Pz electrodes significantly increased with STN-DBS at 130 Hz compared to OFF-stimulation. P300 latency was also significantly increased, though to a lesser degree, over Pz electrode with stimulation at 80 Hz. No significant P300 latency modifications were detected at 60 Hz stimulation compared to OFF-stimulation condition. P300 amplitude did not change significantly for any of the stimulation conditions tested., Conclusions: Low frequency STN-DBS is associated with minor modifications of P300 latency compared to conventional stimulation at 130 Hz, possibly suggesting that 60 and 80 Hz may have less interference with attentive and cognitive processes in PD patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Unexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy., Aims: We evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting., Methods: In this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score., Results: In patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05-5.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85-1.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01-1.09) was significantly associated with a risk of recurrence., Conclusion: ALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Autoimmune Hepatitis (AIH) can present under clinical profile as acute hepatitis of unexplained cause. We analyzed clinical, therapeutical and prognostic implications of AIH presenting as acute hepatitis in a cohort of patients admitted to 3 referral Centres in Italy. AIH onset was considered acute when transaminases were higher than 10 times the normal limit and/or bilirubin higher than 5 mg/ml (irrespectively from the histology, available only in 62% of cases). Among 479 patients diagnosed as AIH, 202 (43%) met the criteria of acute onset. This former group of patients on the basis of the histology has been subdivided in the "genuine" acute onset (83 pts) and acute "on chronic" onset (45 pts) At onset, clinical acute AIH showed significantly higher ALT, bilirubin and INR levels (p < 0.001 for all), lower albumin values (p = 0.001), similar IgG levels; Response to treatment was similar between the two groups. The progression to liver cirrhosis or its complications was significantly less frequent in acute onset AIH (13% vs. 22%, p = 0.02). The "genuine" acute patients showed a higher albumin serum levels (40 vs. 36, p = 0.001), lower INR levels (1.12 vs. 1.26, p = 0.002) and less tendency to the progression of liver disease (7% vs. 12%, p = NS) with respect to acute "on chronic" onset patients. Clinical acute hepatitis represents a common presentation of AIH, responds to standard immunosuppression regimen and would seem to be correlated with a better long-term prognosis., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: To investigate the long-term effects and safety of new direct anti-viral agents (DAAs) in patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) without renal involvement., Methods: The study enrolled 22 consecutive patients, 19 received sofosbuvir-based regimen and three patients received other DAAs, individually tailored according to latest guidelines. As of December 2016, the median length of follow-up was 17 months (range 13-21)., Results: Extra-hepatic manifestations at enrollment were: purpura and arthralgia (12 cases), peripheral neuropathy (10 cases) and marginal zone B- lymphomas (2 cases). After a four-week DAA therapy, all patients became HCV- negative. Moreover, after 48 weeks since the beginning of DAA treatment, sustained regression of purpura and arthralgias was observed respectively in eight and in nine cases; peripheral neuropathy improved in seven cases, and cryocrit median values decreased from three (1-20) at baseline to two (1-12) after 48 weeks. Two cases with indolent marginal zone lymphomas did not show any haematological response: size and number of the involved nodes remained unchanged. In addition, the monoclonal B-cell population found in the peripheral blood in four cases did not disappear after recovery from HCV- RNA. Mild side effects occurred in nine patients, but six patients developed ribavirin-related anaemia requiring reduction of ribavirin dose., Conclusions: DAA therapy is safe and effective to eradicate HCV in MC, but seems associated with satisfactory clinical response in mild or moderate cryoglobulinaemic vasculitis and no response in B-NHL.

The progressively growing knowledge of the pathophysiology of a number of immune-mediated gastrointestinal and liver disorders, including autoimmune atrophic gastritis, coeliac disease, autoimmune enteropathy, inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and autoimmune pancreatitis, together with the improvement of their detection methods have increased the diagnostic power of serum antibodies. In some cases - coeliac disease and autoimmune atrophic gastritis - they have radically changed gastroenterologists' diagnostic ability, while in others - autoimmune hepatitis, inflammatory bowel disease and autoimmune pancreatitis - their diagnostic performance is still inadequate. Of note, serum antibody misuse in clinical practice has raised a number of controversies, which may generate confusion in the diagnostic management of the aforementioned disorders. In this review, we critically re-evaluate the usefulness of serum antibodies as biomarkers of immune-mediated gastrointestinal and liver disorders, and discuss their pitfalls and merits., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Elastography point quantification is a novel non-invasive method for the assessment of liver fibrosis by measuring liver stiffness. The aim of this study was to evaluate the accuracy of elastography point quantification for the diagnosis of liver fibrosis and to assess impact of steatosis on liver stiffness measurement, in a cohort of patients with chronic hepatitis C., Methods: In this single-centre cross-sectional study, 211 consecutive patients with chronic hepatitis C, scheduled for liver biopsy, were examined with the elastography point quantification technology. On the same day, all patients underwent clinical examination, laboratory tests and abdominal ultrasound., Results: The best cut-offs of liver stiffness measurement were 6.16 kPa for the diagnosis of significant fibrosis (≥S3) and 6.79 kPa for advanced fibrosis (≥S4). Areas under the receiver operating characteristic curve were 0.831 (CI: 0.773-0.880) for significant fibrosis, and 0.954 (CI: 0.916-0.978) for advanced fibrosis. Among patients within the same fibrosis stages (S0-S2 and S3-S6; S0-S3 and S4-S6), mean liver stiffness measurement values were similar in patients with steatosis (≥10% at liver biopsy or detected by ultrasound) compared to those without. Discordance between elastography point quantification and histology were affected by the presence of BMI>30 kg/m 2 (P=.047, CI: 0.136-0.988 and P=.020, CI: 0.083-0.812 respectively)., Conclusions: In patients with chronic hepatitis C, elastography point quantification is an accurate non-invasive method for the diagnosis of significant and advanced fibrosis. The presence of obesity is a risk factor for misclassification of significant and advanced liver fibrosis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To evaluate "ex ante" the predictive factors of incomplete/absent response to the standard therapy in a well characterized series of Autoimmune Hepatitis (AIH) patients from Italy., Methods: Of 282 AIH patients screened from our database 166 (59%) had a sustained response and 116 (41%) had an incomplete/absent response to the therapy; all patients were analyzed for the clinical, serological and histological parameters at diagnosis., Results: The patients with incomplete/absent response were characterized by significantly younger age (30 aa vs 42 aa p=0.001) and a significantly higher frequency of cirrhosis at diagnosis than patients who had a complete response to therapy (26% vs 3% p<0.0001); furthermore, patients with incomplete/absent response were distinguished from those with a complete response for significantly lower serum levels of both AST (7.9×upper normal limit [unl] vs 13×unl p<0.005) and ALT (10.9×unl vs 18×unl p=0.002) at diagnosis, and by an increase in IgG serum levels (1.43×unl vs 1.27×unl p=0.009). After stepwise logistic regression, cirrhosis at diagnosis (p=0.003, OR 0.12, 95% CI 0.03-0.49) and younger age (p=0.001, OR 1.03, 95% CI 1.01-1.05) represent two independent variables of incomplete/absent response., Conclusions: Younger age and cirrhosis are predictive of lack of response to the standard therapy in AIH patients., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Patients with autoimmune hepatitis (AIH) can present with symptoms ranging from those that are insidious and nonspecific to acute hepatitis with jaundice. However, some patients have no symptoms at diagnosis and are identified incidentally. We investigated disease progression and outcomes of these 2 groups of patients., Methods: We performed a retrospective study to compare clinical, immunologic, and histologic features and outcomes of patients with asymptomatic vs. symptomatic AIH. We analyzed data collected from 305 patients (90 asymptomatic and 215 with symptoms), diagnosed with AIH from 1994 and 2013, at the Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System in Bologna, Italy., Results: At diagnosis, patients with asymptomatic AIH had significantly lower mean levels of alanine aminotransferase (7.0- ± 8.0-fold the upper limit of normal) than patients with symptomatic disease (23.0- ± 18.0-fold the upper limit of normal; P < .001), and lower mean levels of bilirubin (1.4 ± 1.4 mg/dL vs. 8.6 ± 10.4 mg/dL; P < .001). Asymptomatic patients also had significantly lower histologic grades (7.0 ± 2.5) than symptomatic patients (9.0 ± 2.9; P < .001). However, larger proportions of asymptomatic patients had anti-liver/kidney microsomal antibodies type 1 (26.8% vs. 13.1%; P < .006), and associated autoimmune thyroid (26.7% vs. 12.6%; P = .003) or skin (8.9% vs. 2.3%; P = .010) disorders. Age at onset, sex, response to therapy, disease progression, genetic factors, and other autoantibody markers did not differ between patients with asymptomatic vs. symptomatic disease., Conclusions: Patients with asymptomatic vs. symptomatic AIH have similar courses of disease progression and responses to immunosuppressive agents, and therefore should receive the same treatment. Patients affected by thyroid or dermatologic autoimmune disorders are at increased risk of developing subclinical liver disease, and should be assessed routinely for AIH., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression., Methods: We analysed the Bologna cohort of 216 patients with primary biliary cirrhosis referred to our Centre between 1997 and 2007, according to symptomatic (fatigue and/or pruritus) or asymptomatic presentation. Clinical, biochemical, histological and immunological feature at diagnosis, response to ursodeoxycholic acid and progression of the disorder were compared after a mean follow-up of 81 ± 75 months., Results: At diagnosis, symptomatic patients were significantly more often women (98.6% vs. 87.2%, P = 0.004), younger (mean age 49 ± 12 vs. 55 ± 12 years, P = 0.003) and with more pronounced biochemical activity, as indicated by higher alkaline phosphatase (mean 2.93 ± 2 vs. 2.12, P = 0.002) and aminotransferase (mean 1.92 ± 1 vs. 1.47 ± 1.27, P = 0.014) levels, whereas histological stage and autoantibody profile were similar. Symptomatic patients were less likely to respond to ursodeoxycholic acid therapy (63% vs. 81%, P = 0.006) and developed more often cirrhosis and its complications (31% vs. 13%, P = 0.004)., Conclusions: Fatigue and/or pruritus at onset identify a subset of patients with primary biliary cirrhosis who preferentially are women, younger, with a particularly active disease, less responsive to ursodeoxycholic acid treatment, and more inclined to evolve to cirrhosis and its complications., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Cryoglobulinaemic vasculitis (CV) is often related to hepatitis C virus (HCV) infection, but it can develop in other diseases (e.g. other infections, connective tissue diseases, malignancies) in the absence of HCV infection. A comparison of the performance of the recently published classification criteria for the CV was made between HCV-positive and HCV negative patients with serum cryoglobulins., Methods: 500 patients with serum cryoglobulins were studied. Their mean age was 60.77±13.75 years, they were 356 females (71.2%) and 144 males (28.8%). CV was diagnosed in 272 patients (54.4%), while other diseases associated with serum cryoglobulins without CV (CwV) were diagnosed in 228 patients (45.6%)., Results: 117 HCV negative patients were collected (23.4%) and they were 42/272 (15.4%) among the CV group, while they were 75/228 (32.9%) among the CwV. In HCV negative patients the sensitivity and specificity of the classification criteria of CV were 89.5% CI 95% [79.5-99.5] and 90.3% CI 95% [82.8-97.8], respectively, while in HCV positive patients they were 88.3% CI 95% [83.6%-93.1%] and 96.1% CI 95% [91.8-100], respectively. The most frequent disease recognised among the HCV negative patients was Sjögren's syndrome (SS) (55/117, 47.0%), and the sensitivity and the specificity of the CV classification criteria were 88.9% CI 95% [76.5-100] and 91.3% CI 95% [79.2-100], respectively., Conclusions: The classification criteria for CV showed a good performance even in HCV-unrelated patients. A slightly lower specificity was observed for the classification of HCV-unrelated CV, since some clinical manifestations included in the clinical item for the classification criteria occurred more frequently in HCV-negative rather than HCV-positive controls with CWV.

Objectives: The aim of the present study is to provide information on clinical outcome of the patients affected by HCV-positive mixed cryoglobulinemia (MC) treated with PEG-IFN and Ribavirin for 6 or 12 months according to the HCV genotype., Methods: Eighty-six patients (42 women and 44 men) were enrolled in 8 Italian centres. All the patients had MC in the active phase of the disease. The patients received Peginterferon alfa-2b 1.5 mcg/kg/once a week (QW) and daily oral Ribavirin (800/1,000/1,200) according to their body weight for 48 weeks for genotype 1 and 4 and for 24 weeks for genotypes 2 and 3., Results: In the 44 patients who underwent 12 months of therapy, 17 cases (39%) could be considered as 'non-responders' and 11 relapsed, therefore only 16 patients (36%) obtained a sustained virological response. In the 42 patients who underwent six months of therapy only 7 cases (17%) could be considered as 'non-responders' and 8 relapsed, therefore 27 patients (64%) obtained a sustained virological response. Purpura score dropped in both group (p<5.79 x 10-17) and only 5 cases of the group A (11%) and 5 of the group B (12%) did not show any improvement. Arthralgias showed a similar behaviour. Many patients relapsed after the end of the treatment., Conclusions: This study documents a lower response rate than that observed in the clinical trials with HCV chronic hepatitis, but the presence of comorbidities and older age should be taken into consideration. Most patients (88.5%) showed a complete and persistent recovery from clinical symptoms.

Background: Hepatitis C virus infection frequently leads to chronic hepatitis, possibly evolving to end-stage liver disease and hepatocellular carcinoma. Regulatory T cells can affect antiviral immune response thus influencing the outcome of the disease., Aim: To determine numeric and functional distribution of regulatory T cells expressing CD4+CD25hiFoxp3+ (T-regs) during the different stages of hepatitis C virus-related liver disease., Methods: 90 hepatitis C viraemic patients and 50 healthy controls were included. Surface and intracellular (Foxp3) T-reg markers were evaluated by flow cytometry. Target cell proliferation and interferon-gamma production were evaluated in 37 HCV patients. In 16 cases intrahepatic distribution of Foxp3 by immuno-histochemistry was assessed., Results: T-regs were increased in hepatitis C virus infected patients and correlated inversely with aminotransferases and directly with MELD score and disease duration. A preserved inhibitory ability of interferon-gamma production was distinctive of patients with normal aminotransferases. Circulating T-regs did not correlate with intrahepatic distribution of Foxp3., Conclusions: In chronic hepatitis C, selective expansion of peripheral T-regs in patients with normal aminotransferases and advanced disease suggests that, though a continual low level inflammation does not prevent liver disease progression, once cirrhosis has developed it may represent an attempt to prevent immuno-mediated decompensation., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: During the last decade patients with concomitant clinical, biochemical, immunoserological, and histological features of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) were sporadically described, but definite diagnostic criteria and specific serological markers to support the diagnosis of AIH/PBC overlap syndrome (AIH/PBC OS) are still lacking., Methods: Clinical, biochemical, and histological features, autoantibody profile, and treatment response of 15 patients with coexistent hepatitic and cholestatic liver damage, all fulfilling strict diagnostic criteria for both AIH and PBC, were compared with those of 120 patients with pure PBC and 120 patients with pure AIH., Results: At diagnosis, the AIH/PBC OS patients' median age was 51 years, similar to that of the PBC patients (52 years, P=NS), but significantly higher than that of the AIH patients (40 years, P=0.04). Anti-dsDNA antibodies were detected in 60% of AIH/PBC OS patients, but only in 4% of PBC patients and 26% of AIH patients (P<0.0001 and 0.01, respectively). Double positivity for antimitochondrial antibodies (AMA) and anti-dsDNA was present in 47% of those with AIH/PBC OS, but only in 2% of the pathological controls (P<0.0001; specificity: 98; 95% confidence interval (CI): 97-99.2; positive likelihood ratio: 28; 95% CI: 9.8-79.4). Combined therapy (ursodeoxycholic acid (UDCA) plus steroids) achieved biochemical response in 77% of AIH/PBC OS patients., Conclusions: Concomitant AMA/anti-dsDNA seropositivity can be considered the serological profile of AIH/PBC OS. The combination of UDCA and steroids is effective in achieving persistent biochemical amelioration in most AIH/PBC OS patients.

Autoimmune hepatitis (AIH) is a chronic progressive hepatitis, characterized by interface hepatitis with lymphoplasmacellular infiltrates on liver biopsy, high serum globulin level and circulating autoantibodies. It is classified into two types, according to autoantibody profile: type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscle (SMA) antibodies; type 2 by anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies. AIH affects all ages, may be asymptomatic, frequently has an acute onset, and can present as fulminant hepatitis. The diagnosis of AIH is based on a scoring system codified by an international consensus. Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with AIH and results in remission induction in over 80% of patients. Alternative proposed strategies in patients who have failed to achieve remission on standard therapy or patients with drug toxicity include the use of cyclosporine, tacrolimus, budesonide or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease, however AIH can recur or develop de novo after liver transplantation.

Background: Population-based studies of the natural course of chronic viral liver disease that consider comorbidity factors are lacking. Using data from the Dionysos Study, we quantified the burden of chronic viral liver disease and the role of alcohol intake to morbidity and mortality in a representative sample of subjects from the general population of two communities of Northern Italy., Methods and Findings: We followed up 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) yr, respectively. Ethanol intake was evaluated using a food-frequency questionnaire, fatty liver (FL) was diagnosed by ultrasonography, and liver cirrhosis (LC) and hepatocarcinoma (HCC) were diagnosed by liver biopsy. Exact multivariable Poisson regression was performed to identify predictors of death. The incidence and remission rates of FL were 9.0 and 29.7 in the HCV cohort and 4.0 and 30.4 per 1,000 person-years (PY) in the HBV cohort. Progression to LC and HCC was more common in the HCV than in the HBV cohort (4.5 vs 2.0 and 2.7 vs 2.0 per 1,000 PY, respectively). Ethanol intake was an independent predictor of LC in the HCV cohort [rate ratio (RR) = 4.15 (95% CI 1.02-41.2) for every increase of 30 g/day of ethanol intake at baseline] and of death rate in both cohorts [RR = 8.53 (95% CI 1.40-24.61) and 3.56 (1.34 to 26.50) for every increase of 30 g/day of ethanol intake at baseline]., Conclusions: The morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary-care populations, blood donors, or clinical series. Ethanol intake is an independent predictor of LC in subjects with chronic HCV infection and an independent predictor of death in subjects with either HCV or HBV infection.

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, characteristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs.

Unlabelled: Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%)., Conclusion: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.

Antibodies to liver/kidney microsome type 1 occur in Italian patients with hepatitis C, but rarely develop in North American patients. Our goals were to compare the frequencies of the HLA markers associated with autoimmune expression in Italian and North American patients with chronic hepatitis C and to determine genetic bases for regional differences in antibody production. HLA B8, DR3, DR4, DR7, DR11, DR13, DQ2, and the B8-DR3-DQ2 haplotype were determined by microlymphocytotoxicity and polymerase chain reaction in 105 Italian patients (50 with microsomal antibodies), 100 North American patients (none with microsomal antibodies), and Italian and North American healthy control subjects. Italian patients with microsomal antibodies differed from North American patients without these antibodies by having a higher frequency of HLA DR7 (54% vs. 27%, P=0.002). HLA DR7 occurred more frequently in seropositive Italian patients than in seronegative counterparts (54% vs. 11% P < 0.0001), Italian healthy control subjects (54% vs. 29%, P=0.0009), and North American healthy control subjects (54% vs. 19%, P < 0.0001). The frequency of HLA DR7 was similar in North American patients and controls (27% vs. 19%, P=0.2), but it was lower than in Italian controls (19% vs. 29%, P=0.059). Seropositive Italian patients had a lower frequency of HLA DR11 than seronegative Italian patients and Italian controls (18% vs. 34%, P=0.07, and 18% vs. 35%, P=0.02, respectively). In contrast to seropositive Italian patients, North American patients had HLA DR4 (30% vs. 12%, P=0.02), HLA DR13 (29% vs. 10%, P=0.01), and the B8-DR3-DQ2 haplotype (23% vs. 6%, P=0.01) more often. Similarly, HLA DR4 and the B8-DR3-DQ2 phenotype were more frequent in North American patients than in Italian controls (30% vs. 16%, P=0.005, and 23% vs. 7%, P=0.00002, respectively). HLA DR7 is associated with the development of microsomal antibodies in Italian patients with chronic hepatitis C. The lower frequency of HLA DR7 in North America could contribute to the rarity of these antibodies in this region. HLA DR11 may be protective against the development of microsomal antibodies in Italian patients, whereas HLA DR4, HLA DR13, and the B8-DR3-DQ2 haplotype may be protective in North American patients.

Background: Patients who have refused to provide blood samples has meant that there have been significant delays in confirming outbreaks of Ebola virus hemorrhagic fever (EVHF). During the 2 EVHF outbreaks in the Republic of Congo in 2003, we assessed the use of oral fluid specimens versus serum samples for laboratory confirmation of cases of EVHF., Methods: Serum and oral fluid specimens were obtained from 24 patients with suspected Ebola and 10 healthy control subjects. Specimens were analyzed for immunoglobulin G antibodies by enzyme-linked immunosorbent assay (ELISA) and for Ebola virus by antigen detection ELISA and reverse-transcriptase polymerase chain reaction (RT-PCR). Oral fluid specimens were collected with a commercially available collection device., Results: We failed to detect antibodies against Ebola in the oral fluid specimens obtained from patients whose serum samples were seropositive. All patients with positive serum RT-PCR results also had positive results for their oral fluid specimens., Conclusions: This study demonstrates the usefulness of oral fluid samples for the investigation of Ebola outbreaks, but further development in antibodies and antigen detection in oral fluid specimens is needed before these samples are used for filovirus surveillance activities in Africa.

Background & Aims: Autoimmune thyroid disorders (AITDs) are reported, especially during interferon treatment, in chronic HCV infection, in which non-organ-specific autoantibodies (NOSAs) are common. We wondered whether seropositivity for NOSA is associated with susceptibility to AITDs., Methods: We evaluated thyroid function and antithyroglobulin and antithyroperoxidase antibodies in 348 Italian patients with chronic hepatitis C (34% NOSA-positive), 196 patients (33% NOSA-positive) of whom received interferon treatment., Results: At baseline, thyroid disorders were significantly more frequent in liver/kidney microsomal antibody type 1 (LKM1)-positive patients (29% vs 9%, P < .005). Similarly, on interferon therapy de novo autoimmune thyroid markers and/or symptomatic thyroid disorders appeared more often in LKM1-positive patients (50% vs 3%, P < .0001). Both female sex and LKM1 positivity were predictors of AITD, but only the latter remained significant after logistic regression analysis. Cross-reactivity to all 7 linear epitopes encoding homologous amino acid sequences shared by the HCV polyprotein, CYP2D6 (the LKM1 autoantigen), and thyroperoxidase was detected in 86% LKM1-positive HCV patients with clinical thyroid disorders, but in none of the LKM1-positive or negative HCV patients without thyroid disease, and none of an HCV-negative control group comprising subjects with LKM1-positive autoimmune hepatitis or AITD without liver disease ( P < .0001)., Conclusions: Patients receiving interferon therapy for hepatitis C seropositive for LKM1 are susceptible to develop AITDs, in association with treatment. Molecular mimicry and epitope spreading are potential pathogenic mechanisms.

Aim: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts., Methods: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls., Results: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P = 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P = 0.01) and in controls (16% vs 34%, P = 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P = 0.01)., Conclusion: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.

Background: Hepatitis C virus (HCV)-related chronic hepatitis is frequently associated with non-organ-specific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients., Methods: A total of 143 consecutive adult patients with hepatitis C were studied. Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomal antibody type 1 (LKM1) were detected by indirect immunofluorescence. All patients were treatment naive and received combined antiviral therapy (interferon [IFN]-ribavirin) after enrollment in the study. Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as long-term responders if transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment., Results: Thirty-seven patients (25%) were NOSA positive (SMA was detected in 19 patients, ANA in 10, ANA and SMA in 4, LKM1 in 3, and SMA and LKM1 in 1). The prevalence of long-term response was similar between NOSA-positive patients and NOSA-negative patients (48.6% vs. 56.6%; P=not significant). Compared with HCV genotype 1 (HCV-1), HCV genotypes other than 1 were more often associated with long-term response among NOSA-positive patients (93.3% vs. 30%; P=.0017). The overall rate of long-term response, irrespective of NOSA status, was 54.5%. Detection of HCV-1 and elevated gamma-glutamyl transpeptidase serum levels were independent negative prognostic factors of treatment response (P=.007 and P=.026, respectively)., Conclusions: Combined antiviral treatment (IFN-ribavirin) is safe and effective in NOSA-positive patients with hepatitis C, even if long-term response is less likely in those infected with HCV-1.

We evaluated the prevalence and clinical significance of non-organ-specific autoantibodies (NOSAs) in 47 hepatitis C virus (HCV)-positive children with abnormal alanine transaminase levels and analyzed the association between NOSAs and virus level, genotype, human leukocyte antigen status, and interferon (IFN) response. Forty-two hepatitis B virus (HBV)-positive children and 25 age- and sex-matched healthy children served as control subjects. NOSAs were found in 34% of the HCV-positive children, 12% of the HBV-positive controls, and none of the healthy control subjects. Liver-kidney microsomal antibody type 1 (LKM1) was detected in 11% of the HCV-positive children but in none of the controls. The HCV load was significantly higher in NOSA-negative than in NOSA-positive children. HCV genotype distribution and human leukocyte antigen alleles were similar, irrespective of NOSA status. Long-term response to IFN therapy was achieved by 18% of the NOSA-positive and 55% of the NOSA-negative subjects. Two LKM1-positive children developed acute, self-limited hepatocellular necrosis while receiving IFN therapy. NOSAs are frequently present in children with hepatitis C, who are less likely to benefit from IFN therapy.

Non-organ-specific autoantibodies (NOSAs) are frequently found in patients with hepatitis C virus (HCV) chronic infection. Genetics is likely involved in the development of autoimmune reactivities, and differences in the prevalence of HCV-related autoantibodies among populations of various geographic areas should be expected. We evaluated the prevalence and the clinical impact of NOSAs in a series of HCV-infected patients from southern Italy. We studied 283 consecutive anti-HCV positive patients (162 men, 121 women, mean age 54.5 +/- 13.5 years), 94 of whom were cirrhotics and 189 noncirrhotics. Serum from each patient and from 41 hepatitis B surface antigen (HBsAg)-positive/anti-HCV negative control subjects were tested (dilution 1:40) for autoantibodies by indirect immunofluorescence. Qualitative/quantitative HCV-RNA determinations were also performed. The prevalence of NOSAs was significantly higher in anti-HCV-positive subjects than in HBsAg-positive patients (P < 0.006). Autoantibodies were significantly associated with both cirrhosis (P < 0.0001) and older age (P < 0.05). No significant association between NOSAs and either female gender or virological parameters (HCV-RNA positivity, viral load, and genotype) was found. In conclusion, the autoantibody positivity in HCV-infected patients from southern Italy is significantly related to cirrhosis and older age, although its general prevalence is similar to that reported in populations from the north of the country.