Hepatitis: Bianchi FB

Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB, Anonymous00156. · Department of Internal Medicine, Medical School, Center for Research, Transfer and High Education DENOthe, Center for the Study of Systemic Manifestations of Hepatitis Viruses MaSVE, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #16884964 No free full text.

Abstract: Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.

Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, Nishioka M, Penner E, Anonymous00232. · Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK. · J Hepatol. · Pubmed #15464251 No free full text.

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Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Büschenfelde KH, Zeniya M. · Institute of Liver Studies, King's College Hospital, London, UK. · J Hepatol. · Pubmed #10580593 No free full text.

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Muratori L, Bianchi FB. · No affiliation provided · Ann Ital Med Int. · Pubmed #10920501 No free full text.

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Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D. · Institute of Liver Studies, King's College School of Medicine at King's College Hospital, Denmark Hill, London, UK. · Curr Pharm Des. · Pubmed #18673191 No free full text.

Abstract: Hepatitis C virus (HCV) infection is characterized by a number of autoreactive manifestations, such as autoantibody production, cryoglobulinemia and thyroid disorders. We will analyse critically the mechanisms invoked, and partially documented, to explain such manifestations arising in genetically predisposed individuals exposed to HCV. In particular we will examine the available evidence implicating the virus in lowering the B cell activation threshold, in directly infecting lymphocytes and in inducing self-reactivity through a mechanism of molecular mimicry. We will then move to the HCV related clinical immunopathological manifestations, with a specific attention to the effects of antiviral treatment.

Muratori P, Granito A, Pappas G, Muratori L, Lenzi M, Bianchi FB. · Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum-University of Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti 9, 40138 Bologna, Italy. · Mol Aspects Med. · Pubmed #18067956 No free full text.

Abstract: Autoimmune liver disease (ALD) includes a spectrum of diseases which comprises both cholestatic and hepatitic forms: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and the so called "overlap" syndromes where hepatitic and cholestatic damage coexists. All these diseases are characterized by an extremely high heterogeneity of presentation, varying from asymptomatic, acute (as in a subset of AIH) or chronic (with aspecific symptoms such as fatigue and myalgia in AIH or fatigue and pruritus in PBC and PSC). The detection and characterization of non organ specific autoantibodies plays a major role in the diagnostic approach of autoimmune liver disease; anti nuclear reactivities (ANA) and anti smooth muscle antibodies (SMA) mark type 1 AIH, liver kidney microsomal antibody type 1 (LKM1) and liver cytosol type 1 (LC1) are the serological markers of type 2 AIH; antimitochondrial antibodies (AMA) are associated with PBC, while no specific marker is found in PSC, since anticytoplasmic neutrophil antibodies with perinuclear pattern (atypical p-ANCA or p-ANNA) are also detected in a substantial proportion of type 1 AIH cases. Treatment options rely on immunosoppressive therapy (steroids and azathioprine) in AIH and on ursodeoxycholic acid in cholestatic conditions; in all these diseases liver transplantation remains the only therapeutical approach for the end stage of liver disease.

Bianchi FB, Muratori P, Granito A, Pappas G, Ferri S, Muratori L. · Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum-University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy. · Dig Liver Dis. · Pubmed #17936218 No free full text.

Abstract: After the discovery of HCV in 1989 a great amount of data has been produced in order to identify a possible aetiology for a number of idiopathic diseases, especially those with a suspected immune origin. Many associations have not been confirmed by prospective studies (as in the case of autoimmune hepatitis); other immune abnormalities, such as the emergence of non organ-specific autoantibodies and cryoglobulins, have been reported by many specific studies. To date, the link between HCV and autoreactivity is tentatively explained on the basis of sequence homologies shared by the HCV polyprotein and "self" proteins (such as CYP 2D6, target of anti-LKM1) (molecular mimicry mechanism); a second interpretation relies on the demonstration that the HCV - B lymphocyte interaction is able to induce a polyclonal B cell activation, an important cofactor for the development of clinically relevant B-lymphocyte autoimmune disorders. In this review we will focus on the major aspects of the autoimmune phenomena in HCV-infected patients, their clinical and therapeutical implications.

Guidi M, Muratori P, Granito A, Muratori L, Pappas G, Bianchi FB. · Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Università Alma Mater Studiorum, Policlinico Sant'Orsola-Malpighi, Bologna. · Recenti Prog Med. · Pubmed #16496742 No free full text.

Abstract: The preliminary question regarding the clinical issue of the antiviral therapy in the HCV related chronic hepatitis patients is: is it mandatory the research for the autoantibodies in the eligible patients for the antiviral treatment? This issue is of particular interest at the light of the the reported cases of HCV positive patients with positivity for liver kidney microsome type 1 antibody who developed a hepatitic flare during the antiviral treatment. The data from literature about the efficacy and safety on the antiviral treatment in patients with autoantibodies are few and controversial, particularly if the ones regarding antiviral drugs and more recent treatment regimens are taking into account (peg-interferon, combined therapy of interferon and ribavirin). Large and prospective studies are needed for a thorough evaluation about the potential impact of autoantibodies reactivity on the therapeutic outcome. To date, it must be confirmed that a strict monitoring of hepatic parameters is to recommend during the whole treatment phase. This in the light of a potential appearance of significant flares of aminotransferases, particularly in subjects with anti LKM-1 autoantibodies, during interferon therapy.

Czaja AJ, Bianchi FB, Carpenter HA, Krawitt EL, Lohse AW, Manns MP, McFarlane IG, Mieli-Vergani G, Toda G, Vergani D, Vierling J, Zeniya M. · Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN 55905, USA. · Hepatology. · Pubmed #15690485 No free full text.

Abstract: New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary.

Bianchi FB, Muratori P, Muratori L. · Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti, 9 40138 Bologna, Italy. · Clin Liver Dis. · Pubmed #12362581 No free full text.

Abstract: The molecular characterization of the autoreactivities associated with autoimmune liver disease will improve their diagnosis and enhance understanding of their pathogenic mechanisms. Surprisingly, little is known about the nature of the major autoreactivities associated with type 1 AIH, including homogeneous ANA and antibodies to microfilaments [3]. Type 1 AIH is, however, the prototype of autoimmune liver disease [103].

Bianchi FB, Muratori L. · Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Università degli Studi di Bologna. · Ann Ital Med Int. · Pubmed #10842892 No free full text.

Abstract: Primary autoimmune liver diseases can be hepatitic or cholestatic in nature. Autoimmune hepatitis, more often diagnosed in women, is characterized by biochemical and histological activity, with polyclonal hypergammaglobulinemia as a frequent feature. Antinuclear and anti-smooth muscle antibodies are the serological hallmarks of type 1 autoimmune hepatitis, whereas liver-kidney microsomal antibody type 1 and liver cytosol antibody type 1 designate the type 2 form. Response to immunosuppression is usually excellent. The most frequent cholestatic autoimmune disease is primary biliary cirrhosis, characterized by anti-mitochondrial antibody positivity and typical bile duct lesions observed on liver biopsy. Treatment with biliary acids improves the biochemical picture, may alleviate pruritus, and delays the development of end-stage liver disease. Primary sclerosing cholangitis occurs more frequently in men and affects both the intra- and extrahepatic biliary trees, determining the typical "beading" appearance. Associated inflammatory bowel diseases are often observed. To date, no medical therapy is able to modify the course of this disease. Autoimmune cholangitis is an anti-mitochondrial antibody-negative cholestatic disease with most of the features of primary biliary cirrhosis. "Overlap" syndromes where autoimmune hepatitic and cholestatic features coexist in the same patient, have also been reported. Autoimmune phenomena secondary to hepatitis C virus-related liver disease such as the occurrence of antinuclear, anti-smooth muscle antibodies and liver-kidney microsomal antibody type 1 are often observed.

Zauli D, Cassani F, Bianchi FB. · Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Italy. · Biomed Pharmacother. · Pubmed #10424245 No free full text.

Abstract: Hepatitis C virus (HCV) has been implicated in the development of a variety of autoimmune phenomena, some of which are well documented and include a panel of auto-antibodies shared with autoimmune hepatitis (AIH). Anti-nuclear (ANA) and smooth muscle (SMA) antibodies (markers of AIH type 1 [AIH-1]), have been demonstrated in 9-38% and 5-91% of cases respectively, whereas anti-liver/kidney microsomal type 1 (anti-LKM-1) and anti-liver cytosol type 1 antibodies (anti-LC1) (markers of AIH type 2 [AIH-2]), are definitely rarer, especially in adults. The presence of these auto-reactivities in chronic hepatitis C generates clinical overlaps and dilemmas in the correct classification and treatment of such patients. The immunopathological characterization of the auto-antibodies, anti-nuclear and smooth muscle antibodies in particular, combined with internationally defined criteria for the diagnosis of AIH is helpful in this clinical process. Thyroid auto-antibodies and cryoprecitable rheumatoid factors are also commonly detected in hepatitis C, while the occurrence of other auto-antibodies still awaits confirmation.

Czaja AJ, Muratori P, Muratori L, Carpenter HA, Bianchi FB. · Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Liver Int. · Pubmed #15287855 No free full text.

Abstract: BACKGROUND: Bile duct injury is not a feature of classical autoimmune hepatitis (AIH), but it has been described in variant forms of the disease. AIMS: Our goals were to assess the similarity of AIH with bile duct injury to classical disease and to evaluate the possibility of concurrent primary biliary cirrhosis (PBC). METHODS: Fifteen patients with bile duct injury were compared with 151 patients with classical AIH. Patterns of nuclear immunofluorescence and the frequency and nature of autoantibodies associated with AIH and PBC were determined. RESULTS: Patients with bile duct injury had the same nuclear-staining patterns, frequency and nature of autoantibodies, and genetic risk factors as the comparison group. Features specific for PBC, including the multiple nuclear dot pattern of immunofluorescence and antibodies to the M2 antigens, Sp100 and nuclear pore complex antigen, gp210, did not distinguish them from classical disease. Remission and treatment failure occurred with similar frequencies in both groups. CONCLUSIONS: Patients with AIH and bile duct injury lack features of PBC, and they respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the diagnosis or treatment of AIH.

Granito A, Muratori P, Ferri S, Pappas G, Quarneti C, Lenzi M, Bianchi FB, Muratori L. · Dipartimento di Medicina Clinica, Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Hospital, Padiglione 11, Via Massarenti 9, 40138, Bologna. · Mini Rev Med Chem. · Pubmed #19519509 No free full text.

Abstract: 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.

Muratori P, Granito A, Pappas G, Pendino GM, Quarneti C, Cicola R, Menichella R, Ferri S, Cassani F, Bianchi FB, Lenzi M, Muratori L. · Department of Clinical Medicine, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti, 9, Bologna, Italy. · Am J Gastroenterol. · Pubmed #19491855 No free full text.

Abstract: 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.

Ferri S, Muratori L, Quarneti C, Muratori P, Menichella R, Pappas G, Granito A, Ballardini G, Bianchi FB, Lenzi M. · Department of Clinical Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. · J Hepatol. · Pubmed #19398235 No free full text.

Abstract: BACKGROUND/AIMS: Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. METHODS: Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. RESULTS: At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. CONCLUSIONS: Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.

Muratori P, Granito A, Quarneti C, Ferri S, Menichella R, Cassani F, Pappas G, Bianchi FB, Lenzi M, Muratori L. · Department of Clinical Medicine, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, Via Massarenti, 9, 40138 Bologna, Italy. · J Hepatol. · Pubmed #19395113 No free full text.

Abstract: BACKGROUND/AIMS: Autoimmune hepatitis affects mainly women. It is subdivided into type 1 and type 2 according to the autoantibody profile and without immunosuppression usually evolves to cirrhosis and end-stage liver failure. METHODS: We evaluated clinical, biochemical, immunological and genetic features and treatment response of 163 consecutive Italian patients with autoimmune hepatitis. RESULTS: At diagnosis, type 1 autoimmune hepatitis showed more inflamed liver histology and more pronounced cholestasis, whereas type 2 was more common in children. Male and female patients shared similar clinical, biochemical and immunological features. Of 89 patients with 5-year follow-up or longer, 23 patients irrespective of presenting clinical, biochemical and immunological features achieved complete remission (normal transaminases and gammaglobulin levels) which was maintained with minimal steroid dosage; attempt at treatment withdrawal led to disease exacerbation. Complete responders had more often HLA DRB1*0401 (p = 0.011) and their risk of disease progression was lower (p < 0.0001). CONCLUSIONS: Type 1 and type 2 autoimmune hepatitis is one and the same disease. Autoimmune hepatitis has similar features in male and female patients. HLA DRB1*0401 positive patients are more likely to achieve complete remission. Continuous low-dose steroids are necessary to maintain remission, significantly reducing the risk of disease progression.

Lodato F, Berardi S, Gramenzi A, Mazzella G, Lenzi M, Morelli MC, Tame MR, Piscaglia F, Andreone P, Anonymous00108, Ballardini G, Bernardi M, Bianchi FB, Biselli M, Bolondi L, Cescon M, Colecchia A, D'Errico A, Del Gaudio M, Ercolani G, Grazi GL, Grigioni W, Lorenzini S, Pinna AD, Ravaioli M, Roda E, Sama C, Vivarelli M. · Department of Digestive Diseases and Internal Medicine, Azienda Ospedaliero-Universitaria Policlinico Sant'Orsola-Malpighi, Bologna, Italy. · Aliment Pharmacol Ther. · Pubmed #18549463 No free full text.

Abstract: BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. AIM: To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. METHODS: Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 micro/kg/week plus RBV 8-10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). RESULTS: Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02-106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. CONCLUSIONS: Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with > or =2 log10 drop in HCV-RNA at week 24.

Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW, Anonymous00035. · Department of Medicine, University Medical Centre Hamburg Eppendorf, Germany. · Hepatology. · Pubmed #18537184 No free full text.

Abstract: Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff > or =6) and 81% sensitivity and 99% specificity (cutoff > or =7) in the validation set. CONCLUSION: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher.

Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Ferri S, Quarneti C, Cipriano V, de Molo C, Lenzi M, Chapman RW, Bianchi FB. · Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy. · Aliment Pharmacol Ther. · Pubmed #17767467 No free full text.

Abstract: BACKGROUND: Primary biliary cirrhosis (PBC) may be associated with various rheumatological disorders. AIM: To investigate the frequency and significance of 'rheumatological' antinuclear antibodies in the field of autoimmune chronic liver disease, with special regard to PBC. METHODS: We studied 105 patients with PBC, 162 autoimmune liver disease controls (type 1 and 2 autoimmune hepatitis, primary sclerosing cholangitis), 30 systemic lupus erythematosus and 50 blood donors. Sera were tested for the presence of antibodies to extractable nuclear antigens (anti-ENA) by counterimmunoelectrophoresis, enzyme-linked and immunoblot (IB) assay, and for the presence of anti-centromere antibodies (ACA) by indirect immunofluorescence on HEp-2 cells and IB. RESULTS: The overall prevalence of IB-detected anti-ENA in PBC (30%) was higher than in type 1 autoimmune hepatitis (2.5%, P < 0.0001), type 2 autoimmune hepatitis (0%, P < 0.0001) and primary sclerosing cholangitis (11.5%, P = 0.006) and lower than in systemic lupus erythematosus (53%, P = 0.03). The most frequent anti-ENA reactivity in PBC was anti-SSA/Ro-52kD (28%). ACA were detected by IB in 21% PBC patients and never in the other subjects (P < 0.0001). Anti-SS-A/Ro/52kD positive PBC patients had at the time of diagnosis a more advanced histological stage (P = 0.01) and higher serum levels of bilirubin (P = 0.01) and IgM (P = 0.03) compared with negative ones. CONCLUSIONS: In the autoimmune liver disease setting, anti-SS-A/Ro-52kD and ACA have a high specificity for PBC and can thus be of diagnostic relevance in anti-mitochondrial antibodies negative cases. If confirmed in further studies with adequate follow-up, anti-SS-A/Ro-52kD antibodies might identify PBC patients with a more advanced and active disease.

Muratori P, Czaja AJ, Muratori L, Granito A, Guidi M, Ferri S, Volta U, Mantovani W, Pappas G, Cassani F, Lenzi M, Bianchi FB. · Department of Internal Medicine, Cardioangiology, Hepatology, Policlinico Sant'Orsola-Malpighi, Bologna, Italy. · Dig Dis Sci. · Pubmed #17160474 No free full text.

Abstract: 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.

Grassi A, Quarneti C, Ravaioli M, Bianchini F, Susca M, D'Errico A, Piscaglia F, Tamè MR, Andreone P, Grazi G, Galli S, Zauli D, Pinna AD, Bianchi FB, Ballardini G. · Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna-Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Liver Transpl. · Pubmed #17031825 links to  free full text

Abstract: The aim of this study was to evaluate how the immunohistochemical detection of liver hepatitis C virus (HCV) antigens (HCV-Ag) could support the histologic diagnosis and influence the clinical management of post-liver transplantation (LT) liver disease. A total of 215 liver specimens from 152 HCV-positive patients with post-LT liver disease were studied. Histologic coding was: hepatitis (126), rejection (34), undefined (24; coexisting rejection grade I and hepatitis), or other (31). The percentage of HCV-Ag infected hepatocytes were evaluated, on frozen sections, by an immunoperoxidase technique. HCV-Ag were detectable early in 57% of cases within 30 days post-LT, 92% of cases between 31 and 180 days, and 74% of cases after more than 180 days. Overall, HCV-Ag were detected more frequently in histologic hepatitis as compared to rejection (P < 0.0001) with a higher percentage of positive hepatocytes (P < 0.00001). In 16 patients with a high number of HCV-Ag-positive hepatocytes (65%; range 40-90%) a clinical diagnosis of recurrent hepatitis (RHC) was made despite inconclusive histopathologic diagnosis. Multivariate analysis identified the percentage of HCV-Ag-positive hepatocytes and the time post-LT as independent predictors for RHC (P = 0.008 and P = 0.041, respectively) and the number of HCV-Ag-positive hepatocytes >/=50% as the only independent predictor for nonresponse (P < 0.001) in 26 patients treated with alpha-interferon plus ribavirin. In conclusion, HCV reinfection occurs early post-LT, reaching its peak within 6 months. Immunohistochemical detection of post-LT HCV reinfection support the diagnosis of hepatitis when the histologic features are not conclusive. A high number of infected cells, independently from the genotype, represents a negative predictive factor of response to antiviral treatment.

Vannini A, Cheung K, Fusconi M, Stammen-Vogelzangs J, Drenth JP, Dall'Aglio AC, Bianchi FB, Bakker-Jonges LE, van Venrooij WJ, Pruijn GJ, Zendman AJ. · Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, and Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. · Ann Rheum Dis. · Pubmed #16984940 No free full text.

Abstract: BACKGROUND: Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored. OBJECTIVES: To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). METHODS: Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control). RESULTS: The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples. CONCLUSIONS: In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrulline-independent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.

Muratori P, Sutherland SE, Muratori L, Granito A, Guidi M, Pappas G, Lenzi M, Bianchi FB, Pandey JP. · Department of Internal Medicine, Alma Mater Stadiorum-University of Bologna, Italy. · J Virol. · Pubmed #16641304 links to  free full text

Abstract: GM and KM allotypes-genetic markers of immunoglobulin (Ig) gamma and kappa chains, respectively-are associated with humoral immunity to several infection- and autoimmunity-related epitopes. We hypothesized that GM and KM allotypes contribute to the generation of autoantibodies to liver/kidney microsomal antigen 1 (LKM1) in hepatitis C virus (HCV)-infected persons. To test this hypothesis, we characterized 129 persons with persistent HCV infection for several GM and KM markers and for anti-LKM1 antibodies. The heterozygous GM 1,3,17 23 5,13,21 phenotype was significantly associated with the prevalence of anti-LKM1 antibodies (odds ratio, 5.13; P=0.002), suggesting its involvement in this autoimmune phenomenon in HCV infection.

Granito A, Muratori L, Muratori P, Pappas G, Guidi M, Cassani F, Volta U, Ferri A, Lenzi M, Bianchi FB. · Department of Internal Medicine, Cardioangiology, and Hepatology, Alma Mater Studiorum, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. · J Clin Pathol. · Pubmed #16505279 links to  free full text

Abstract: AIMS: To evaluate the diagnostic significance of anti-filamentous actin antibodies (A-FAA) assessed with a commercial ELISA in comparison with immunofluorescence reactivity and patterns of anti-smooth muscle antibodies (SMA); and to correlate A-FAA positivity with clinical, immunogenetic, laboratory, and histological features in patients with autoimmune hepatitis type 1 (AIH-1). METHODS: We studied 78 consecutive untreated AIH-1 patients and 160 controls: 22 with autoimmune hepatitis type 2 (AIH-2), 51 with hepatitis C, 17 with coeliac disease (CD), 20 with primary biliary cirrhosis (PBC) and 50 blood donors. SMA was evaluated by indirect immunofluorescence (IIF) on frozen sections of rat tissues, and A-FAA with a modified commercial ELISA. RESULTS: SMA was detected by IIF in 61 (78%) of 78 AIH-1 patients, of whom 47 (60%) had the SMA-T/G and 14 (18%) the SMA-V pattern. Of the pathological controls, 32 (20%) had the SMA-V pattern (25 with hepatitis C, 2 with AIH-2, 2 with PBC, 3 with CD). A-FAA were present in 55 AIH-1 patients (70.5%; 46 with SMA-T/G, 7 with SMA-V, and 2 SMA-negative), and in 10 controls (6%), of whom five had hepatitis C, two AIH-2, two PBC and one CD. The association between A-FAA and the SMA-T/G pattern was statistically significant (p<0.0001). A-FAA levels were higher in SMA-T/G positive than SMA-V positive AIH-1 patients and controls (p<0.0001). A-FAA positivity was significantly associated with higher gamma-globulin and IgG levels, but did not correlate with other considered parameters. CONCLUSION: The modified A-FAA ELISA strictly correlates with the SMA-T/G pattern and is a reliable and operator independent assay for AIH-1. Detection of A-FAA, even if devoid of prognostic relevance, may be useful when interpretative doubts of standard IIF arise.