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Pierluigi Toniutto

pierluigi.toniutto@uniud.it

Journal articles

2009
 
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PMID 
Pierluigi Toniutto, Rosalba Minisini, Carlo Fabris, Tullia De Feo, Francesca Marangoni, Michela Burlone, Claudio Avellini, Davide Bitetto, Ezio Fornasiere, Elisa Fumolo, Umberto Baccarani, Mario Pirisi (2009)  Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression.   Clin Transplant 23: 2. 184-190 Mar  
Abstract: Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti-core antibodies may develop overt "de novo" HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O-HBV). In the native liver, 8/30 patients had detectable O-HBV; during the follow-up, O-HBV infection was demonstrated in 14 graft specimens. Graft O-HBV was associated with older donor age (> or =50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O-HBV and no O-HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post-transplant O-HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged < or =40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O-HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.
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Francesca Ferrara, Paolo Ventura, Alberto Vegetti, Maria Guido, Gianluca Abbati, Elena Corradini, Giovanna Fattovich, Carlo Ferrari, Mara Tagliazucchi, Anna Carbonieri, Alessandra Orlandini, Stefano Fagiuoli, Sara Boninsegna, Eliseo Minola, Giovanna Rizzo, Fabio Belussi, Martina Felder, Marco Massari, Gabriele Pozzato, Stefania Bonetto, Pierangelo Rovere, Carla Sardini, Athos Borghi, Maria Luisa Zeneroli, Pierluigi Toniutto, Elisabetta Rossi, Antonello Pietrangelo (2009)  Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C.   Am J Gastroenterol 104: 3. 605-616 Mar  
Abstract: OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.
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Carlo Fabris, Pierluigi Toniutto, Edmondo Falleti, Elisabetta Fontanini, Annarosa Cussigh, Davide Bitetto, Ezio Fornasiere, Elisa Fumolo, Claudio Avellini, Rosalba Minisini, Mario Pirisi (2009)  MTHFR C677T polymorphism and risk of HCC in patients with liver cirrhosis: role of male gender and alcohol consumption.   Alcohol Clin Exp Res 33: 1. 102-107 Jan  
Abstract: BACKGROUND: A single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified. The TT or CT genotypes show a marked reduction of the enzyme activity; this causes higher homocysteine levels and alterations of folate metabolism. Folate metabolism is essential for DNA synthesis and methylation, crucial steps in carcinogenesis. In this paper, we investigated whether the MTHFR C677T SNP could influence the occurrence of hepatocellular carcinoma (HCC) in a cohort of patients transplanted for end stage liver disease of different etiologies. METHODS: Two hundred and twelve consecutive patients who underwent liver transplantation for end stage liver disease due to hepatitis B or C, alcoholic liver disease, and other causes were studied. Two hundred and thirty-six blood donors served as controls. Focal hepatic lesions were searched in the sectioned explanted livers. The presence of the MTHFR C677T SNP was determined via polymerase chain reaction amplification. RESULTS: Among the 65 patients with HCC, 22 had the CC genotype, 30 the CT, and 13 the TT genotype. Only in patients with alcoholic liver disease was a significant association detected between the TT genotype and the presence of liver cancer (6/17 vs. 5/46, p < 0.05). At stepwise logistic regression analysis the independent selected predictors of HCC were found: age at transplantation >55 years (p < 0.001) and the association among male gender, alcoholic liver disease, and MTHFR TT genotype (p = 0.002). CONCLUSIONS: The present study suggests that male TT carriers with alcoholic cirrhosis bear an increased risk of developing HCC.
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Rossano Girometti, Sergio Giuseppe Intini, Lorenzo Cereser, Massimo Bazzocchi, Giuseppe Como, Matteo Del Pin, Umberto Baccarani, Pierluigi Toniutto, Chiara Zuiani (2009)  Incidental pancreatic cysts: a frequent finding in liver-transplanted patients as assessed by 3D T2-weighted turbo spin echo magnetic resonance cholangiopancreatography.   JOP 10: 5. 507-514 09  
Abstract: CONTEXT: The increasing frequency of incidental pancreatic cysts at imaging is a challenging topic due to the uncertainty of the aggressiveness of these lesions, especially small ones. To date, no data exist about their prevalence in a population of liver-transplanted patients. OBJECTIVE: To determine the prevalence of incidental pancreatic cysts in liver-transplanted patients using magnetic resonance cholangiopancreatography. DESIGN: A retrospective, single center case series. SETTING: A tertiary referral centre. Interventions and patients Seventy-two examinations were performed over a two-year period in 47 liver-transplanted patients suspected for biliary complications. MAIN OUTCOME MEASURES: Prevalence of incidental pancreatic cysts; proportion of cyst evolution over time; association of cysts with clinical and imaging features. RESULTS: The prevalence of pancreatic cysts was 59.6%. Analysis showed a mean diameter of 5.4 mm and the presence of 1-3 cysts in 78.6% of patients (22/28). Communication with the main pancreatic duct was identified for 28 relatively larger cysts (up to 14 mm) in 14 subjects. An "intraductal papillary mucinous neoplasia-like pattern" was observed in 12 patients with cysts, based on the number of cysts, dimensions, and distribution. Out of the 15 patients who underwent additional MRCPs to monitor biliary findings, only one patient with proven intraductal papillary mucinous neoplasia showed modification of the cysts at follow-up. Among the evaluated pre- or post-transplantation factors (sex, age, etiology of cirrhosis, pre-transplant hepatocarcinoma, pancreatic abnormalities other than cysts, type of pancreaticobiliary channel/biliary anastomosis, presence of biliary complications, lithiasic biliary complications, transplant-examination interval), only the alcoholic etiology of cirrhosis was associated with the prevalence of pancreatic cysts (P=0.006). CONCLUSIONS: Incidental pancreatic cysts are frequent in liver-transplanted patients. Clinical significance, relation to transplant, impact on patient management before and after transplant are still under debate and a matter for further investigation.
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Carlo Fabris, Carlo Smirne, Stefano Fangazio, Pierluigi Toniutto, Michela Burlone, Rosalba Minisini, Davide Bitetto, Edmondo Falleti, Andrea Cerutti, Mario Pirisi (2009)  Influence of angiotensin-converting enzyme I/D gene polymorphism on clinical and histological correlates of chronic hepatitis C.   Hepatol Res 39: 8. 795-804 Aug  
Abstract: Aim: This study aimed to verify the relationship between the insertion-deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) and clinical and histological correlates of chronic hepatitis C. Methods: Two-hundred and fifty-eight, treatment naive, unselected hepatitis C virus (HCV) RNA-positive patients and 210 controls were studied. ACE allelic variants were determined by polymerase chain reaction. Results: Mean staging scores adjusted for age, body mass index (BMI) and alcohol consumption were: men, D/* = 2.283; men, I/I = 2.092; women, D/* = 2.241; and women, I/I = 3.283 (P = 0.028). Age-adjusted mean BMI were: men, D/* = 25.01; men, I/I = 24.87; women, D/* = 23.73; and women, I/I = 22.50 (P = 0.006). Age and BMI-adjusted mean low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) cholesterol ratios were: men, D/* = 2.344; men, I/I = 2.283; women, D/* = 1.916; and women, I/I = 1.903 (P = 0.004). Histological grading correlated positively with triglycerides and negatively with HDL and LDL cholesterol (P < 0.0001). Conclusion: Female ACE I/I homozygotes have higher liver fibrosis scores in comparison to D/* women and to men; moreover, they are leaner and have a lower LDL/HDL cholesterol ratio. These observations suggest a possible mutual influence between ACE polymorphism, serum lipid concentrations and outcome of chronic HCV infection.
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Davide Rossi, Lisa Sala, Rosalba Minisini, Carlo Fabris, Edmondo Falleti, Michaela Cerri, Michela Emma Burlone, Pierluigi Toniutto, Gianluca Gaidano, Mario Pirisi (2009)  Occult hepatitis B virus infection of peripheral blood mononuclear cells among treatment-naive patients with chronic lymphocytic leukemia.   Leuk Lymphoma 50: 4. 604-611 Apr  
Abstract: Recent guidelines emphasise the risk of hepatitis B virus (HBV) reactivation among patients with hematologic malignancies of B lineage, in which HBV has been recently hypothesised to play a pathogenetic role. We aimed to determine the prevalence of occult HBV infection (OBI) of peripheral blood mononuclear cells, defined as detection of sequences from >or=2 HBV genes in subjects lacking hepatitis B surface antigen, among patients with treatment-naive chronic lymphocytic leukemia (CLL). HBV DNA sequences from four HBV genes (S, X, core and pol) were searched for in archival material obtained at diagnosis (N = 173), and from age and sex-matched controls. OBI was observed in 17/173 (10%) patients and 5/173 (3%) controls (OR = 3.6, 95% CI 1.37-9.79, p = 0.014). OBI was not associated with differences on 5-year survival and biological predictors, but patients with CLL with OBI had significantly lower peripheral blood lymphocyte count. After 8 years of observation without treatment, one OBI positive patient with CLL converted into positive HBsAg serology and developed active hepatitis. In conclusion, OBI is significantly more prevalent among patients with CLL than in age and sex-matched controls, and may contribute to the susceptibility of patients with CLL to HBV reactivation, whether exposed or not to biological agents.
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Cinzia Borgogna, Pierluigi Toniutto, Carlo Smirne, Barbara Azzimonti, Massimo Rittà, Claudio Avellini, Carlo Fabris, Santo Landolfo, Marisa Gariglio, Mario Pirisi (2009)  Expression of the interferon-inducible proteins MxA and IFI16 in liver allografts.   Histopathology 54: 7. 837-846 Jun  
Abstract: AIMS: To test the hypothesis that the activation of the interferon (IFN) system pathways might link hepatitis C virus (HCV) recurrence in the liver allograft with acute cellular rejection. METHODS AND RESULTS: In this retrospective study, allograft biopsy specimens from 28 adult patients (14 HCV+ and 14 HCV-) who had undergone their first liver transplantation were analysed. Eleven biopsy specimens showed acute cellular rejection (Banff rejection activity index score > or =3). Specimens were immunostained for two IFN-inducible proteins, MxA and IFI16, and for CD45. The predominant MxA reactivity pattern was hepatocytic, whereas IFI16 was expressed in both the hepatocellular and inflammatory compartments. Moderate to strong MxA expression in hepatocytes was associated positively with rejection score (P < 0.01), donor's age < or =45 years (P < 0.05) and aspartate aminotransferase levels >40 U/l on the day of biopsy (P < 0.05), and inversely with infiltration of portal triads by IFI16+/CD45+ cells (P < 0.005) and time to progression beyond Ishak stage 2 of recurrent hepatitis C (P < 0.01). On multivariate analysis, MxA expression in hepatocytes was independently associated with allograft rejection and donor's age. CONCLUSIONS: Acute allograft rejection and recurrence of HCV infection in the liver allograft appear to intersect in the IFN system pathways.
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U Baccarani, G L Adani, D Serraino, D Lorenzin, M Gambato, A Buda, G Zanus, A Vitale, P Piselli, A De Paoli, V Bresadola, A Risaliti, P Toniutto, U Cillo, F Bresadola, P Burra (2009)  De novo tumors are a major cause of late mortality after orthotopic liver transplantation.   Transplant Proc 41: 4. 1303-1305 May  
Abstract: The purpose of this study was to describe de novo post-orthotopic liver transplantation (OLT) malignancies for comparison with incidence rates in Italian cancer registries. Three hundred thirteen OLT patients engrafted from 1991 to 2006 and surviving 12 months without a previous diagnosis of cancer were evaluated for the development of de novo malignancies excluding nonmelanoma skin cancers. During a total follow-up time of 1753 PYs, 40 (12.8%) de novo malignancies were diagnosed in 40 recipients. The most common cancers were non-Hodgkin lymphoma (NHL; 20%), cancer of the head and neck (17%), Kaposi sarcoma (KS; 17%), and esophageal tumors (12%). The 1-, 3-, 5-, and 10-year estimated survival rates were 70%, 56%, 48%, and 39%. Patients with de novo cancers showed a lower 10-years survival rate (P = .0047) than patients without (39% vs 75%). The risk of cancer after OLT was 3-fold higher than that of the general population of the same age and gender (95% confidence interval [CI], 2.0-4.3). De novo tumor sites or types with significantly elevated standardized incidence ratios (SIRs) included KS (SIRs = 212), NHL (SIRs = 13.7), oesophagus (SIRs = 18.7), melanoma (SIRs = 10.1), and head and neck cancers (SIRs = 4.6). Tumors after OLT were associated with lower long-term survival, confirming that cancer is a major cause of late mortality.
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Baccarani, Piselli, Serraino, Adani, Lorenzin, Gambato, Buda, Zanus, Vitale, De Paoli, Cimaglia, Bresadola, Toniutto, Risaliti, Cillo, Burra (2009)  Comparison of de novo tumours after liver transplantation with incidence rates from Italian cancer registries.   Dig Liver Dis Jun  
Abstract: AIM: The purpose of this study is to describe de novo post-liver transplant malignancies and compare their frequency with incidence rates from Italian cancer registries. PATIENTS AND METHODS: Four hundred and seventeen patients subjected to liver transplantation, from 1991 to 2005, surviving for at least 30 days and without a previous diagnosis of cancer (including hepatocellular carcinoma), were evaluated for the development of de novo malignancies excluding non-melanoma skin cancers. RESULTS: During a total follow-up time of 2856 person-years, 43 de novo malignancies were diagnosed in 43 liver transplantation recipients (10.3%). The most common cancers were non-Hodgkin lymphoma (9 cases), cancer of the head and neck (8 cases), Kaposi's sarcoma (6 cases) and esophageal carcinoma (5 cases). The 1, 3, 5 and 10 years estimated survival rates were 69%, 57%, 53% and 42%. Patients with de novo cancers had a lower 10-year survival rate than patients without cancers (58% versus 76%, p=0.005). The risk of cancer after liver transplantation was nearly 3-fold higher than that of the general population of the same age and sex (95% CI: 1.9-3.6). De novo tumour sites or types with significantly elevated SIR included Kaposi's sarcoma (SIR=144), non-Hodgkin lymphoma (SIR=13.8), esophagus (SIR=23.4), head and neck cancers (SIR=7) and cervix uteri (SIR=30.7). CONCLUSIONS: Tumours after liver transplantation are associated with lower long-term survival, confirming that cancer is a major cause of late mortality in liver transplantation.
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U Baccarani, G L Adani, M Isola, C Avellini, D Lorenzin, A Rossetto, G Currò, C Comuzzi, P Toniutto, F Soldano, V Bresadola, A Risaliti, F Bresadola (2009)  Steatosis of the graft is a risk factor for posttransplantation biliary complications.   Transplant Proc 41: 4. 1313-1315 May  
Abstract: BACKGROUND: Despite recent advances in organ preservation, immunosuppression, and surgical techniques, the biliary tree is still considered the Achilles' heel of liver transplantation. The aim of this study was to retrospectively analyze the incidence of biliary complications and identify predisposing risk factors. METHODS: From January 2004 to December 2007, 117 consecutive deceased donor liver transplantations were retrospectively analyzed for the development of biliary complications by review of medical records. Patients were divided into group 1 with biliary complications (n = 43) and group 2 without biliary complications (n = 74). RESULTS: The overall biliary complication rate was 36.8%; leakage 6% and stricture 30.8%. Univariate analysis indicated that significant predictors of biliary complications were the time interval between portal and arterial reperfusion (P = .037) and macrovacuolar steatosis of the graft >25% (P = .004). A stepwise logistic regression model demonstrated that >25% macrosteatosis of the graft was the only independent risk factor predicting biliary complications after liver transplantation (odds ratio [OR] = 5.21; CI 95% [1.79-15.15]; P = .002). No differences were noted in patient or graft survival between the 2 groups. CONCLUSION: Transplantation of a liver with >25% steatosis was a risk factor for the development of a biliary complication.
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2008
 
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Pierluigi Toniutto, Carlo Fabris, Elisa Fumolo, Davide Bitetto, Ezio Fornasiere, Edmondo Falleti, Rachele Rapetti, Rosalba Minisini, Mario Pirisi (2008)  Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation.   Liver Transpl 14: 7. 1014-1019 Jul  
Abstract: Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained <20 mug/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P < 0.01), the increase in the body mass index after LT (P < 0.01), a low serum cholesterol concentration (P = 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P < 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Factors associated with FAGA include the cumulative steroid dose, weight changes after LT, and ACTH and cholesterol levels at the time of steroid withdrawal.
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Carlo Fabris, Carlo Smirne, Pierluigi Toniutto, Cosimo Colletta, Rachele Rapetti, Rosalba Minisini, Edmondo Falleti, Monica Leutner, Mario Pirisi (2008)  Usefulness of six non-proprietary indirect markers of liver fibrosis in patients with chronic hepatitis C.   Clin Chem Lab Med 46: 2. 253-259  
Abstract: BACKGROUND: The aim of the study was to perform a comprehensive diagnostic evaluation of six popular, non-proprietary, indirect markers of liver fibrosis in a cohort of patients with chronic hepatitis C representing the full spectrum of disease severity. METHODS: A total of 167 consecutive, hepatitis C virus RNA positive, untreated patients with chronic hepatitis C were studied. Liver biopsy with histological evaluation and age/platelet index, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, Bonacini's discriminant score, Forn's fibrosis index and FibroIndex were assessed in all patients. RESULTS: The area under the receiver operating characteristic curves of the six tests was always greater when performed to discriminate patients with METAVIR score F4 than when assessed to discriminate patients with METAVIR score > or =F2. At step-wise discriminant analysis the only indirect marker of fibrosis entered was FibroIndex, with the following correct classification of the patients: total=52.1, patients with scores F0-F1=62.2, patients with scores F2-F3=26.0 and patients with score F4=68.4. CONCLUSIONS: The ability to correctly classify patients using a panel of non-proprietary indirect markers of liver fibrosis is far from being ideal. Among them, FibroIndex appears to possess the best discriminating capacity. The simultaneous use of several indirect markers of liver fibrosis does not improve their diagnostic accuracy.
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Pierluigi Toniutto, Carlo Fabris, Edmondo Falleti, Annarosa Cussigh, Elisabetta Fontanini, Davide Bitetto, Ezio Fornasiere, Rosalba Minisini, Tullia De Feo, Francesca Marangoni, Mario Pirisi (2008)  Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C.   Liver Int 28: 2. 257-263 Feb  
Abstract: BACKGROUND/AIMS: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, being a putative steatogenic factor, may promote liver fibrosis progression in patients with chronic hepatitis C. This study aimed to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent HCV after orthotopic liver transplantation (OLT). METHODS: We studied 63 such patients, followed for >1 year. MTHFR allelic variants were determined by a polymerase chain reaction/restriction fragment length polymorphism method. RESULTS: Recipients carrying the TT genotype had more frequently, 1-year post-OLT, homocysteine serum levels >23 micromol/L (P<0.05), serum triglycerides >180 mg/dL (P<0.02) and de novo diabetes mellitus (P<0.05) but not a higher frequency of graft steatosis. Time-to-event analysis in reaching an Ishak staging score >2 was performed by stratifying the recipients as follows: (a) patients with donor age < or =45 years, (b) patients with donor age >45 and C/(*) genotype, and (c) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: (a) 8/37, (b) 10/19 and (c) 6/7 (P=0.0005). CONCLUSION: The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion.
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Rossano Girometti, Alessandro Furlan, Gennaro Esposito, Massimo Bazzocchi, Giuseppe Como, Franca Soldano, Miriam Isola, Pierluigi Toniutto, Chiara Zuiani (2008)  Relevance of b-values in evaluating liver fibrosis: a study in healthy and cirrhotic subjects using two single-shot spin-echo echo-planar diffusion-weighted sequences.   J Magn Reson Imaging 28: 2. 411-419 Aug  
Abstract: PURPOSE: To investigate the relevance of increasing b-values in evaluating liver fibrosis through the agreement of two diffusion-weighted (DW) sequences. MATERIALS AND METHODS: A total of 29 cirrhotic patients and 29 healthy volunteers were studied on a 1.5T system. Two single-shot spin-echo echo-planar sequences were acquired using sets of increasing b-values: 0, 150, 250, and 400 seconds/mm(2) (first sequence: DW1a) and 0, 150, 250, 400, 600, and 800 seconds/mm(2) (second sequence: DW2a). Apparent diffusion coefficients (ADCs) of the hepatic parenchyma were calculated on ADC maps. Noise-scaled single-point ADCs were calculated for each sequence from b = 400 seconds/mm(2). RESULTS: ADCs resulted significantly lower in cirrhotic patients compared to controls using both DW1a (mean 1.14 +/- 0.20 x 10(-3)mm(2)/second vs. 1.54 +/- 0.12 x 10(-3)mm(2)/second; P < 0.0001) and DW2a (mean 0.91 +/- 0.18 x 10(-3)mm(2)/second vs. 1.04 +/- 0.18 x 10(-3)mm(2)/second; P = 0.0089). DW1 and DW2, respectively significantly differed in diagnostic performance at receiver operating characteristic (ROC) curve analysis (P = 0.003), showing AUCs of 0.93 (sensitivity 89.7%, specificity 100%) and 0.73 (sensitivity 62.1%, specificity 79.3%), respectively. Noise-scaled single-point ADCs showed a progressive convergence to similar values in cirrhotic and healthy livers at b = 800 seconds/mm(2) (1.12 +/- 0.27 x 10(-3)mm(2)/second vs. 1.13 +/- 0.17 x 10(-3)mm(2)/second). CONCLUSION: A DW sequence is accurate in assessing liver fibrosis using intermediate (400 seconds/mm(2)) rather than high (800 seconds/mm(2)) maximum b-values, but after proper recalculation of ADCs the effects of perfusion rather than diffusion should be considered responsible for the higher accuracy at lower b-values.
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Piero Stratta, Carlo Smirne, Stefano Fangazio, Cristina Cornella, Elisa Lazzarich, Rosalba Minisini, Pierluigi Toniutto, Carlo Fabris, Cristina Barbé, Mario Pirisi (2008)  ACE genotype, body weight changes and target organ damage in renal transplant recipients.   J Nephrol 21: 6. 879-886 Nov/Dec  
Abstract: BACKGROUND: Carriage of the angiotensin-converting enzyme (ACE) D-allele favors weight gain in mid-life and, possibly, cardiovascular complications; we aimed to verify the relationship between these conditions and ACE polymorphisms in the renal transplant (RTx) setting. METHODS: ACE genotypes were evaluated in 169 RTx recipients (107 males, 62 females) and related to body mass index (BMI; kg/m2) changes 1 year after transplant, as well as to cardiovascular events and allograft loss. Allelic frequencies and body weights were compared with those of a control group (age- and sex-matched healthy blood donors). RESULTS: Allelic frequencies were 0.639 and 0.669 for the D-allele, and 0.361 and 0.331 for the I-allele, in recipients and controls, respectively (p=NS). In the patient population, carriage of the I/ allele was associated with a BMI >23 at the time of RTx (p<0.005). In contrast, in the control group, higher BMI values tended to occur in D/ carriers. Moreover, BMI values were higher in the control group (24.7 -/+ 3.5 vs. 23.6 -/+ 3.3, p=0.003) but, 1 year after RTx, this difference was nullified. At multivariate analysis, the factors associated with weight gain after RTx were ACE D/D (odds ratio [OR] = 2.35, 95% confidence interval [95% CI], 1.00-5.49) and age at RTx <or=49 years (OR=2.82, 95% CI, 1.30-6.13); the factors associated with cardiovascular events and/or allograft loss were cyclosporine-based immunosuppressive regimen (p=0.002), history of smoking (p=0.005) and dyslipidemia (p<0.05). Conclusion: Body weight at the time of RTx and weight gain 1 year after RTx, but not cardiovascular complications and allograft loss, are related to the ACE I/D genotype of RTx recipients.
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Edmondo Falleti, Carlo Fabris, Pierluigi Toniutto, Elisabetta Fontanini, Annarosa Cussigh, Davide Bitetto, Ezio Fornasiere, Claudio Avellini, Rosalba Minisini, Mario Pirisi (2008)  TGF-beta1 genotypes in cirrhosis: relationship with the occurrence of liver cancer.   Cytokine 44: 2. 256-261 Nov  
Abstract: This study aimed to verify whether specific single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta1 (TGF-beta1) may predispose to end-stage liver disease and/or hepatocellular carcinoma (HCC). One hundred eighty-eight consecutive patients transplanted for liver cirrhosis (HBV N=21, HCV N=68, alcoholic N=55 and others N=23) and a control group of 140 healthy blood donors were investigated. Four SNPs were studied by restriction fragment length assays: -800G>A, -509C>T, Leu10Pro and Arg25Pro. Patients were found to possess the -509T/ * (TT 53/188, CT 85/188, CC 50/188 vs TT 22/140, CT 61/140, CC 57/140; p<0.002) and Arg25Pro C/ * genotypes (CC 1/188, CG 31/188, GG 156/188 vs CC 0/140, CG 13/140, GG 127/140; p<0.05) more frequently than controls. Patients with cirrhosis complicated by HCC possessed more frequently the Leu10Pro T/ * genotype than patients without HCC (TT 20/54, CT 26/54, CC 8/54 vs TT 31/134, CT 69/134, CC 34/134; p<0.05). The analysis of molecular variance detected significant genotypic differentiations between controls and cirrhotics but not between cirrhotics with or without HCC. In conclusion, TGF-beta1 SNPs probably facilitate the development of liver cirrhosis, while they seem to have a limited role in predicting the occurrence of HCC.
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Pierluigi Toniutto, Carlo Fabris, Davide Bitetto, Elisa Fumolo, Ezio Fornasiere, Mario Pirisi (2008)  R-1626, a specific oral NS5B polymerase inhibitor of hepatitis C virus.   IDrugs 11: 10. 738-749 Oct  
Abstract: Roche Holding AG is developing R-1626, an oral nucleoside inhibitor of HCV RNA polymerase. R-1626 has been demonstrated to be well absorbed and rapidly converted to the active component R-1479. The compound has demonstrated a strong capacity to inhibit HCV replication in vitro and in vivo, without the rapid development of viral resistance. After 4 weeks of treatment with R-1626 in combination with PEG-IFN plus ribavirin in treatment-naïve patients with genotype 1 HCV infection, HCV RNA could no longer be detected in approximately 74% of patients, compared with 5% of patients treated with PEG-IFN plus ribavirin alone, indicating the high potency of R-1626 to induce HCV RNA viral load reductions. R-1626 was generally well tolerated, although severe side effects of neutropenia were observed at high doses. A phase IIb clinical trial was ongoing at the time of publication to test the efficacy of R-1626 in combination with a standard or lower dose of PEG-IFN and ribavirin in HCV genotype 1-infected patients. Given its potent antiviral effect with an apparent high genetic barrier, R-1626 represents an important advancement in improving the outcome of patients with chronic HCV infection.
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Pierluigi Toniutto, Carlo Fabris, Davide Bitetto, Ezio Fornasiere, Elisa Fumolo, Rachele Rapetti, Mario Pirisi (2008)  Antiviral treatment in patients with hepatitis C virus-related cirrhosis awaiting liver transplantation.   Ther Clin Risk Manag 4: 3. 599-603 Jun  
Abstract: End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.
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2007
 
PMID 
Pierluigi Toniutto, Carlo Fabris, Davide Bitetto, Ezio Fornasiere, Rachele Rapetti, Mario Pirisi (2007)  Updates on antiviral therapy for chronic hepatitis C.   Discov Med 7: 37. 27-32 Feb  
Abstract: Hepatitis C virus (HCV) infection is a major public health problem around the world and it is estimated that there are about 200 million infections globally. The majority of HCV infected patients develop chronic infection, which can progress to liver cirrhosis, hepatocellular carcinoma, and liver failure. Since the discovery of the virus in 1989, impressive progress has been made in the treatment of HCV hepatitis. However, the actual standard of care in treating HCV infection, represented by the combination therapy of pegylated interferon alpha 2a or 2b with ribavirin, fails to cure near half of treated patients. This paper aimed to trace a brief overview of the progress made by interferon-based treatments for HCV hepatitis since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.
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Edmondo Falleti, Carlo Fabris, Pierluigi Toniutto, Elisabetta Fontanini, Annarosa Cussigh, Maja Caldato, Elisabetta Rossi, Davide Bitetto, Rosalba Minisini, Carlo Smirne, Mario Pirisi (2007)  Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C.   J Interferon Cytokine Res 27: 3. 239-246 Mar  
Abstract: To ascertain whether single nucleotide polymorphisms (SNPs) regulating the expression of interferon-gamma (IFN-gamma), IFN-gamma receptor-1 (IFNGR-1), interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-alpha (TNF-alpha) may be associated with early fibrosis progression of recurrent hepatitis C, 50 liver transplantation recipients (32 men, 18 women, median age 56 years) with a median histologic follow-up time of 54 months were studied; 98 healthy blood donors served as controls. Cytokine SNPs were determined by means of previously described PCR-based methods. On the basis of the SNP studies, a low, intermediate, or high producer cytokine phenotype was attributed to each patient. Only 1 of the 17 low IL-10 producers reached an Ishak staging score > 2, in contrast to 20 of the 33 patients who were intermediate or high IL-10 producers (Mantel-Cox, p < 0.005). Recipients who were low IL-10 producers and high IFN-gamma producers had significantly slower fibrosis progression in comparison to intermediate/high IL-10 producers and low IFN-gamma producers (p < 0.005). In conclusion, cytokine SNPs resulting in high and low producer phenotypes of both Th1 and Th2 cytokines appear to modulate the course of recurrent hepatitis C. Low IL-10 producers are those with the slowest histologic fibrosis progression.
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PMID 
Pierluigi Toniutto, Carlo Fabris, Davide Bitetto, Ezio Fornasiere, Rachele Rapetti, Mario Pirisi (2007)  Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus.   Curr Opin Investig Drugs 8: 2. 150-158 Feb  
Abstract: Idenix Pharmaceuticals Inc and Novartis AG are codeveloping valopicitabine dihydrochloride, a once-daily oral nucleoside for the potential treatment of HCV infection. In January 2005, a phase IIa clinical trial comparing valopicitabine dihydrochloride with pegylated IFN in treatment-naive HCV patients was ongoing, in addition to a phase IIb trial in patients that had previously failed pegylated IFN and ribavirin combination therapy. In January 2006, an international phase III trial in treatment-refractory patients was planned for the first half of the year, with a phase III trial in treatment-naive individuals planned for the second half of the year.
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Pierluigi Toniutto, Carlo Fabris, Davide Bitetto, Edmondo Falleti, Claudio Avellini, Elisabetta Rossi, Carlo Smirne, Rosalba Minisini, Mario Pirisi (2007)  Role of AST to platelet ratio index in the detection of liver fibrosis in patients with recurrent hepatitis C after liver transplantation.   J Gastroenterol Hepatol 22: 11. 1904-1908 Nov  
Abstract: BACKGROUND AND AIM: Per protocol annual liver biopsy represents the gold standard in the assessment of graft fibrosis progression due to recurrent hepatitis C after liver transplantation. Non-invasive liver fibrosis tests have been proposed as surrogate markers of liver fibrosis in hepatitis C virus (HCV)-positive immune-competent patients. No data are available in the literature on the usefulness of non-invasive liver fibrosis tests in liver transplanted patients with recurrent HCV infection. METHODS: A total of 102 annual per protocol liver biopsies performed in 51 consecutive HCV-positive recipients (31 men), with a follow-up period lasting up to 5 years, were included and evaluated in this study. At each time point, the following non-invasive liver fibrosis tests were calculated: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, AST to platelet ratio index (APRI), Forns' fibrosis index and Bonacini's discriminant score. RESULTS: In discriminating patients with histological fibrosis score >2, APRI provided the best area under the receiver operating characteristic curves (AUROC) (0.801), in comparison to the other four non-invasive liver fibrosis tests. The AUROC of APRI was better in female (0.871) than in male (0.753) recipients. Among female recipients, an APRI value >1.4 was 91% sensitive and 75% specific in detecting a staging score >2. The corresponding values among male recipients were 60% and 77%, respectively. CONCLUSIONS: Among non-invasive liver fibrosis tests, APRI has the highest diagnostic value in discriminating liver transplanted patients with progression to significant liver fibrosis, although its accuracy is influenced by recipient sex.
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Carlo Fabris, Pierluigi Toniutto, Davide Bitetto, Rosalba Minisini, Ezio Fornasiere, Carlo Smirne, Mario Pirisi (2007)  Sex-related influence of angiotensin-converting enzyme polymorphisms on fibrosis progression due to recurrent hepatitis C after liver transplantation.   J Gastroenterol 42: 7. 543-549 Jul  
Abstract: BACKGROUND: Experimental evidence and clinical studies suggest that the renin-angiotensin system and its inhibitors may play a role in regulating the mechanisms of liver fibrosis development. The present study aimed to verify whether carriage of specific angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) allelic variants, modulating angiotensin II generation, could affect the outcome of recurrent hepatitis C after liver transplantation, via several metabolic pathways. METHODS: Forty-five (29 men) recipients, with a median histological follow-up of 60 months after orthotopic liver transplantation (OLT), were studied. ACE gene I/D polymorphism was assessed by means of a polymerase chain reaction procedure. Fibrosis progression was evaluated annually during the follow-up. RESULTS: Weight gain 1 year post-OLT (defined as an increase in body mass index, BMI, of >0.5 kg/m(2)) was significantly more common among D/ carriers (22/22 vs. 16/23, P < 0.005); patients who 1 year after OLT had an increase in their BMI value of >0.5 kg/m(2) more frequently had a triglycerides/cholesterol ratio of <or= 0.7 (16/22 vs. 8/23, chi-squared test P < 0.02). This association was stronger in men. Female D/D homozygotes had the highest probability of showing significant liver fibrosis (7/10) in comparison with men (11/29) and I/ women (1/6) (P < 0.01). CONCLUSIONS: In patients with recurrent hepatitis C, carriers of the D allele appeared to gain more weight after liver transplantation, and in male liver recipients, the D allele was associated with a peculiar lipid profile that was associated with a slower rate of allograft fibrosis progression. Among female recipients, carriage of the D allele may favor more severe allograft fibrosis.
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R Girometti, A Furlan, M Bazzocchi, F Soldano, M Isola, P Toniutto, D Bitetto, C Zuiani (2007)  Diffusion-weighted MRI in evaluating liver fibrosis: a feasibility study in cirrhotic patients.   Radiol Med 112: 3. 394-408 Apr  
Abstract: PURPOSE: This study was designed to establish whether the measurement of apparent diffusion coefficients (ADCs) is clinically accurate in diagnosing liver fibrosis in a selected series of cirrhotic patients. MATERIALS AND METHODS: Twenty-eight cirrhotic patients (mean age 58.1 years) with histologically proven liver fibrosis and 29 healthy controls (mean age 43.8 years) underwent liver diffusion-weighted magnetic resonance (MR) using a 1.5-Tesla (T) magnet equipped with a phased-array coil. Diffusion studies with parallel imaging [generalized autocalibrating partially parallel acquisitions (GRAPPA)] were performed within a single breath-hold using a single-shot spin-echo echo-planar sequence (TE 74 ms) using four b values: b=0, 150, 250 and 400 s/mm(2). A unidirectional diffusion gradient was applied. ADCs were measured on ADC maps. RESULTS: Mean ADC was significantly lower in cirrhotic livers than in controls (1.11+/-0.16 vs. 1.54+/-0.12.10(-3)mm(2)/s) (p<0.0001). Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.96 [confidence interval (CI) 95%:(0.87; 0.94)], demonstrating higher sensitivity and specificity (92.9% and 100%, respectively) for an ADC cutoff of 1.31.10(-3)mm(2)/s. Positive predictive value (PPV), negative predictive value (NPV) and overall accuracy were 100%, 99.9% and 96.4%, respectively. CONCLUSIONS: Diffusion-weighted MRI is an accurate tool in evaluating advanced liver fibrosis if an optimised single-shot spin-echo echo-planar sequence with maximum intermediate b value is used. The ADC threshold for liver fibrosis was 1.31.10(-3)mm(2)/s.
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2006
 
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Carlo Fabris, Carlo Smirne, Pierluigi Toniutto, Cosimo Colletta, Rachele Rapetti, Rosalba Minisini, Edmondo Falleti, Mario Pirisi (2006)  Assessment of liver fibrosis progression in patients with chronic hepatitis C and normal alanine aminotransferase values: the role of AST to the platelet ratio index.   Clin Biochem 39: 4. 339-343 Apr  
Abstract: OBJECTIVES: To verify the value of indirect serum markers in the non-invasive assessment of liver fibrosis in patients with persistently normal or near normal alanine aminotransferases levels (NALT). DESIGN AND METHODS: Forty HCV RNA positive, untreated patients with NALT (30 non-drinkers) underwent two liver biopsies, with a median interval of 78.5 months. The AST/ALT ratio, age-platelet index, AST to platelet ratio index (APRI), Forns fibrosis index and Bonacini's discriminant score were simultaneously determined. RESULTS: In 19 patients, worsening of fibrosis was observed at the second biopsy in comparison to the index biopsy. Among non-drinkers, an APRI >0.4 had a 100% sensitivity in identifying subjects with significant liver fibrosis (Ishak staging score >2) and an APRI < or =0.4 had a 100% negative predictive value in excluding significant liver fibrosis. CONCLUSIONS: APRI performs better, in comparison to all other markers, in correctly classifying patients with NALT with no progression to significant liver fibrosis.
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Pierluigi Toniutto, Carlo Fabris, Mario Pirisi (2006)  Antiviral treatment of hepatitis C.   Expert Opin Pharmacother 7: 15. 2025-2035 Oct  
Abstract: Therapy of hepatitis C virus (HCV) infection may prevent progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease. The cornerstone of treatment has long been standard IFN-alpha, the use of which was associated with a sustained biochemical and viral response in only a small proportion of patients. More recently, the success of interferon-based regimens has substantially improved due to the combination with the guanosine analogue ribavirin and to the advent of pegylated interferon formulations. However, even the most up-to-date regimens fail to cure the infection in many cases and are limited by side effects and high costs. A better understanding of the HCV genomic organisation, the elucidation of the three-dimensional structures of virally encoded enzymes and the recent development of a HCV-replicon system in human hepatoma (Huh-7) cells have led to significant advances in the development of new antiviral compounds, many of which are under evaluation in clinical trials. The aim of this review is to trace a brief overview of the progress made by interferon-based treatments for hepatitis C since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.
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Pierluigi Toniutto, Mario Pirisi, Carlo Fabris, Luca Apollonio, Kalliopi Sereti, Ettore G Bartoli (2006)  The significance of the furosemide test for predicting ascites control by diuretics in cirrhotics: a comparison with volume expansion and octreotide infusion.   Dig Dis Sci 51: 11. 1992-1997 Nov  
Abstract: To verify prospectively the usefulness of the furosemide-induced natriuresis test in predicting ascites control by medical treatment, 15 stable cirrhotics (9 male) with ascites were studied. Sodium excretion was measured after this test and after volume expansion with saline associated with intravenous infusion of octreotide; 6 months later, response to medical treatment was rated as good (N=9) or poor (N=6). Patients with poor ascites control had lower sodium excretion with the furosemide-induced natriuresis test (median, 88 vs 201 mmol; P < 0.01). Poor control was observed in four of four patients with sodium excretion < or =125 mmol, and good control in six of six patients with sodium excretion >175 mmol (P < 0.002). Volume expansion was followed by limited natriuresis (median, 20 mmol), in inverse relationship with plasma active renin concentration (P < 0.001). In conclusion, long-term ascites control is well predicted by the furosemide-induced natriuresis test.
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2005
 
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Cosimo Colletta, Carlo Smirne, Carlo Fabris, Pierluigi Toniutto, Rachele Rapetti, Rosalba Minisini, Mario Pirisi (2005)  Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases.   Hepatology 42: 4. 838-845 Oct  
Abstract: The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (> or = F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 x 10(6) copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.
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PMID 
Pierluigi Toniutto, Carlo Fabris, Rosalba Minisini, Luca Apollonio, Elisabetta Fumo, Maya Caldato, Carlo Smirne, Mario Pirisi (2005)  Weight gain after liver transplantation and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene.   Transplantation 79: 10. 1338-1343 May  
Abstract: BACKGROUND: Subjects who carry the D allele of the angiotensin-converting enzyme (ACE) gene have higher plasma and tissue angiotensin II levels, possibly concurrent with the development of obesity. In transplant recipients, treatment with calcineurin antagonists would magnify these effects. The present study verifies whether the allelic variants of ACE are a factor involved in excess weight gain after liver transplantation. METHODS: A consecutive series of 108 liver transplant recipients (73 males) were studied. Recipient ACE genotypes, determined by a polymerase chain reaction-based method, were related to body mass changes 1 year after transplant. RESULTS: Body mass index (BMI) increased from the pretransplant value of 25.1+/-3.3 kg/m2 to 25.9+/-3.5 kg/m2 (P<0.005). The difference was mainly attributable to recipients carrying 1 D allele or more (N=88) in whom the BMI increased from 25.3+/-3.1 kg/m2 to 26.3+/-3.3 kg/m2 (P<0.005). A BMI of 25 kg/m or greater was measured in 30 of 45 deletion/deletion homozygotes and 25 of 43 insertion/deletion heterozygotes; in contrast, 14 of 20 insertion/insertion homozygotes had a normal body mass (P<0.01). Among patients with normal body mass pretransplant (N=56), none of 13 insertion/insertion homozygotes reached a BMI value 25 kg/m or greater posttransplant (P<0.005). At multivariate analysis, pretransplant body mass and carriage of 1 D allele or more were independent predictors of body mass gain greater than 2 kg/m. CONCLUSIONS: Carriage of the D allele of the ACE gene is a strong, independent risk factor for excess weight gain after liver transplantation.
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Pierluigi Toniutto, Carlo Fabris, Elisabetta Fumo, Luca Apollonio, Maya Caldato, Claudio Avellini, Rosalba Minisini, Mario Pirisi (2005)  Pegylated versus standard interferon-alpha in antiviral regimens for post-transplant recurrent hepatitis C: Comparison of tolerability and efficacy.   J Gastroenterol Hepatol 20: 4. 577-582 Apr  
Abstract: BACKGROUND: In the treatment of hepatitis C virus (HCV) infection, regimens including pegylated interferon-alpha are superior to those including standard interferon; the present retrospective study was performed to verify whether the same is applicable to biopsy-proven recurrent hepatitis C (genotype 1b) after liver transplantation (OLT). METHODS: Twenty-four patients (16 male) were studied. Twelve had received interferon-alpha(2b) (IFN), 9 MU weekly and 12 received pegylated interferon-alpha(2b) (PEG-IFN), 0.5 microg/kg weekly. All had received oral ribavirin 600-800 mg/day. Treatment duration was intended for 12 months. A repeat liver biopsy, with evaluation of the Ishak grading and staging scores, was obtained at 1 year. RESULTS: Only 12/24 patients (50%) completed a full year of therapy; 17 (71%) experienced side-effects requiring a 50% dosage reduction or discontinuation of the IFN, PEG-IFN and/or ribavirin. This was observed in 6/12 patients (50%) treated with IFN in comparison to 11/12 patients (92%) treated with PEG-IFN (P < 0.05). The difference was mainly accounted for by anemia and leukopenia that were reported in 4/12 IFN patients (33%) versus 9/12 PEG-IFN patients (75%; P < 0.05), respectively. End-of-treatment viral response (ETVR) and histological response were always associated and occurred in 4/24 patients (17%), two in each treatment arm. Patients with ETVR were younger, had always completed 1 year of therapy, had had recurrent hepatitis later after transplantation and presented a higher baseline grading score. CONCLUSIONS: In the OLT setting, the potential benefits of antiviral treatments including PEG-IFN may be limited by the poor tolerability of the adopted drugs.
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G L Adani, U Baccarani, A Risaliti, M Sainz-Barriga, D Lorenzin, G Costa, P Toniutto, G Soardo, D Montanaro, P Viale, G Della Rocca, F Bresadola (2005)  A single-center experience of late retransplantation of the liver.   Transplant Proc 37: 6. 2599-2600 Jul/Aug  
Abstract: Liver retransplantation is considered to carry a higher risk than primary transplantation. However, there are an increasing number of retransplant candidates, especially owing to late graft failure. The aim of this study was to analyze a single-center experience in late liver retransplantation. The overall rate of primary retransplantation was 11.4% (28 re-OLT out of 245 primary OLT); the 14 (52%) who underwent retransplantation at more than 3 months after the first transplant were analyzed by a medical record review. Causes of primary graft failure leading to retransplantation were chronic hepatic artery thombosis in five cases (36%); recurrent HCV cirrhosis in four cases (29%); chronic rejection in two cases (14%); veno-occlusive disease; hepatic vein thrombosis or idiopathic graft failure in one case each (7%). UNOS status at re-OLT was always 2A, all patients were hospitalized; three were intensive care unit bound. ICU and total hospital stay had been 7 +/- 5 and 28 +/- 16 days, respectively. One- and 2-year patient and graft survivals were 84% and 62% and 67% and 67%, respectively. Death occurred in four patients. Two out of the three recovered in ICU at the time of retransplantation, at a median interval of 15 +/- 9 days after retransplantation. The survival rate after late retransplantation is improving, and this option should be considered to be a efficient way to save lives, especially by defining the optimal timing for retransplantation.
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Carlo Fabris, Pierluigi Toniutto, Davide Bitetto, Rosalba Minisini, Carlo Smirne, Maya Caldato, Mario Pirisi (2005)  Low fibrosis progression of recurrent hepatitis C in apolipoprotein E epsilon4 carriers: relationship with the blood lipid profile.   Liver Int 25: 6. 1128-1135 Dec  
Abstract: BACKGROUND: The histological outcome of chronic hepatitis C is better among carriers of the apolipoprotein E (ApoE) epsilon4 allele, for reasons unknown. The orthotopic liver transplantation (OLT) setting allows to separate the role played by liver-derived ApoE (graft) from ApoE of different origin (recipient). Patients and METHODS: Forty-six OLT recipients with recurrent hepatitis C were studied. Grafts and recipients were genotyped for ApoE. In a follow-up extending up to 4 years, the serum triglycerides-to-cholesterol ratio (T/C ratio) was measured 1 year after OLT, whereas fibrosis progression was assessed yearly and expressed as fibrosis units/month (FU/mo). RESULTS: A T/C ratio < or =0.75 was observed in 13/15 cases in which both donor and recipient were epsilon4 carriers, 10/19 cases in which epsilon4 alleles were of exclusive recipient's origin and 5/12 cases in which epsilon4 alleles were of exclusive donor's origin or absent (P<0.02). One year after OLT, a fibrosis progression < or =0.100 FU/mo was associated with a low T/C ratio (24/34 vs. 4/12, P<0.05). An Ishak staging score >2 was reached later by male recipients who were epsilon4 carriers (P<0.002). CONCLUSIONS: Recipient's carriage of ApoE epsilon4 affects fibrosis progression of recurrent hepatitis C through gender-specific mechanisms, associated with a peculiar, ApoE-associated, lipid profile.
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M Sainz-Barriga, U Baccarani, L Scudeller, A Risaliti, P L Toniutto, M G Costa, M Ballestrieri, G L Adani, D Lorenzin, V Bresadola, G Ramacciatto, F Bresadola (2005)  Quality-of-life assessment before and after liver transplantation.   Transplant Proc 37: 6. 2601-2604 Jul/Aug  
Abstract: BACKGROUND: Quality-of-life (QoL) assessment includes health status, disability, psychological wellness, and social performance. We sought to evaluate the effect of liver transplantation (OLT) on the QoL of patients awaiting the procedure and its variations up to 8 years afterwards. METHODS: LEIPAD-perceived QoL and BSI-psychological distress tests were used. Patients were divided in four groups (waiting list patients, 1 to 2 years after LT, 3 to 4 years after LT, 5 to 8 years after LT). Patients were also evaluated for type and severity of liver disease. RESULTS: We evaluated 126 patients, 71% male, 29% female, median age 60.7 years (range 40 to 76 years), median follow-up 4 years (range 1 to 8). The patients on the waiting list scored worse both in global stress index (GSI) and total LEIPAD scores than transplanted patients. Upon univariate linear regression analysis, the only dimension associated with time groups was LEIPAD--physical functioning, showing a progressive improvement of perceived physical status with time from transplant. Severity of liver disease showed a protective effect, probably reflecting a better control of stressful events from patients transplanted at advanced stages of liver disease. Protective effects were found for male sex, retired, cohabitant patients, and the degree of education. Housewife and widow patients showed negative associations with BSI and LEIPAD dimensions. No independent predictors of QoL were found in this study. CONCLUSIONS: OLT improves most, but not all, QoL and psychological distress domains.
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Pierluigi Toniutto, Carlo Fabris, Claudio Avellini, Rosalba Minisini, Davide Bitetto, Elisabetta Rossi, Carlo Smirne, Mario Pirisi (2005)  Excess body weight, liver steatosis, and early fibrosis progression due to hepatitis C recurrence after liver transplantation.   World J Gastroenterol 11: 38. 5944-5950 Oct  
Abstract: AIM: To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft. METHODS: Ninety consecutive patients (63 males, median age 53 years; 55 with HCV-related liver disease), transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single, experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis. The SFP was quantified in fibrosis units/month (FU/mo). The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it. RESULTS: In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point, a SFP <=0.100 FU/mo was observed more frequently among recipients who had received their graft from a young donor and had a pre-transplant BMI value >26.0 kg/m(2). At completion of the first post-transplant year, a BMI value >26.5 kg/m(2) was associated with a T/C ratio <=1. The proportion of patients with SFP >0.100 FU/mo descended in the following order: female recipients with a high T/C ratio, male recipients with high T/C ratio, and recipients of either gender with low T/C ratio. Hepatic steatosis was observed more frequently in recipients who, in the first post-transplant year, had increased their BMI >=1.5 kg/m(2) in comparison to the pre-transplant value. Hepatic steatosis was inversely associated with the staging score. CONCLUSION: Among HCV positive recipients, excess weight gain post-OLT does not represent a factor favoring early liver fibrosis development and might even be protective against it.
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2004
 
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U Baccarani, G L Adani, P Toniutto, M Sainz, D Lorenzin, P L Viale, G Ramacciato, A Risaliti, F Bresadola (2004)  Liver transplantation from old donors into HCV and non-HCV recipients.   Transplant Proc 36: 3. 527-528 Apr  
Abstract: BACKGROUND: Chronic liver failure due to HCV-related cirrhosis is the leading indication for liver transplantation in Western countries. Inferior long-term results have been reported for liver transplantation in HCV patients, especially when marginal donor livers are utilized. The aim of this study was to retrospectively analyze the outcome of liver transplantation from elderly donors in HCV versus non-HCV recipients. METHODS: One hundred seventy-nine patients receiving 204 liver transplantations were divided into four groups according to HCV positivity and donor age (> or <65 years). Long-term survivals were calculated by the Kaplan-Meier method. RESULTS: Grafts from donors of >65 years into HCV-positive patients displayed lower patient and graft survival rates than HCV-negative cases, although macrosteatosis was more frequent (55% vs 9%, P =.02) among organs used for non-HCV cases. Moreover, HCV-positive recipients transplanted with a donor aged >65 years had significantly lower patient and graft survival (40% vs 78% [P =.01] and 40% vs 68% [P =.06], respectively) than patients receiving a liver from a younger donor. CONCLUSIONS: Our retrospective analysis, although hampered by a small number of patients transplanted with an old liver, suggest that the results of liver transplantation with a donor graft >65 years of age into an HCV-positive recipient shows a worse outcome than those from younger donors. Older livers should be reserved for non-HCV cases.
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Pierluigi Toniutto, Elisabetta Fumo, Maja Caldato, Luca Apollonio, Antonella Perin, Mario Pirisi (2004)  Favourable outcome of adefovir-dipivoxil treatment in acute de novo hepatitis B after liver transplantation.   Transplantation 77: 3. 472-473 Feb  
Abstract: Adefovir-dipivoxil has been shown to be effective against lamivudine-resistant mutants in immunocompetent patients and in a small number of liver transplant recipients with recurrent hepatitis B virus (HBV) infection. The therapeutic role of adefovir-dipivoxil in acute de novo HBV infection after transplantation is uncertain. We describe a case of acute de novo HBV infection that occurred after liver transplantation and that was treated with lamivudine followed (when viral escape mutants emerged) by adefovir-dipivoxil rescue. Treatment outcome was excellent, with complete viral clearance and development of a protective titer of antibodies to anti-hepatitis B surface antigen. Because the donor was vaccinated against HBV, it is conceivable that clearance of HBV infection in the recipient might have been favored by adoptive transfer of immunity to HBV. The immune status of the donor might be a factor to consider when determining the treatment options for de novo hepatitis B.
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M Sainz-Barriga, U Baccarani, A Risaliti, D Gasparini, M Sponza, G L Adani, P L Toniutto, C Avellini, G Ramacciato, F Bresadola (2004)  Successful minimally invasive management of late portal vein thrombosis after splenectomy due to splenic artery steal syndrome following liver transplantation: a case report.   Transplant Proc 36: 3. 558-559 Apr  
Abstract: Portal vein thrombosis (PVT) after liver transplantation (OLT), which occurs in 1% to 2.7% of cases, can compromise patient and graft survival. Percutaneous transhepatic portal vein angioplasty offers an option to treat PVT, diminishing surgically related morbidity and the need for retransplantation. We describe a case of late PVT after OLT, which was successfully treated by a minimally invasive percutaneous transhepatic approach using both mechanical fragmentation and pharmacologic lysis of the thrombus followed by anticoagulation. The patient has had a good clinical course with normal graft function and patent portal blood flow at 6-month follow-up. This case report confirms the possibility of successful recanalization of the portal vein in a patient with late PVT after liver transplantation. Sustained anticoagulation/antiaggregation therapy for at least 6 months after the procedure is advisable.
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PMID 
Pierluigi Toniutto, Carlo Fabris, Elisabetta Fumo, Luca Apollonio, Maya Caldato, Laura Mariuzzi, Claudio Avellini, Rosalba Minisini, Mario Pirisi (2004)  Carriage of the apolipoprotein E-epsilon4 allele and histologic outcome of recurrent hepatitis C after antiviral treatment.   Am J Clin Pathol 122: 3. 428-433 Sep  
Abstract: Carriage of the epsilon4 allelic variant of the apolipoprotein E (ApoE) gene might affect the outcome of hepatitis C virus (HCV) infection. The liver transplantation setting offers the opportunity to verify the role of the donor's vs recipient's ApoE polymorphism. Twenty-four patients (16 men) with recurrent hepatitis C, all infected by HCV-1b and treated with interferon and ribavirin, were genotyped for ApoE variants. Liver biopsies were done at baseline and 12 months later After treatment, staging scores improved in 10 of 24 patients. Staging improvement was associated with recipient sex, completion of the full antiviral schedule, and recipient's epsilon4 carriage. The beneficial effect of epsilon4 carriage toward the progression of fibrosis was due entirely to the contribution given by male patients and was independent of the viral response. Recipients', but not donors', carriage of at least 1 epsilon4 allele might be associated with a better histologic outcome in recurrent HCV infection.
Notes:
 
DOI   
PMID 
Pierluigi Toniutto, Carlo Fabris, Nadia Bortolotti, Rosalba Minisini, Claudio Avellini, Elisabetta Fumo, Mario Pirisi (2004)  Evaluation of donor hepatic iron concentration as a factor of early fibrotic progression after liver transplantation.   J Hepatol 41: 2. 307-311 Aug  
Abstract: BACKGROUND/AIMS: Hepatic iron may act as an important co-morbid factor in non-hemochromatotic liver diseases, but whether it may favour fibrogenesis after liver transplantation is not known. To verify whether the hepatic iron concentration of the graft might play a role in the rapid fibrotic progression frequently observed after liver transplantation for chronic hepatitis C. METHODS: The hepatic iron concentration, measured at the time of the donor operation, was retrospectively related to the histological follow-up data of 68 recipients (49 males, 19 females), of whom 38 were hepatitis C virus positive. RESULTS: The hepatic iron concentration in donor liver biopsies ranged from 25 to 7,100 microg/gdw. After a median follow-up of 19 months, nine patients (five HCV positive) had a staging score >3. There was a significant association between a higher frequency of increasing staging and donor age >50 years. In female HCV-positive recipients, a graft hepatic iron concentration >1,200 microg/gdw was associated with fibrosis progression >0.15 fibrosis units per month (4/4 vs. 1/7, p<0.01). CONCLUSIONS: The graft hepatic iron concentration may be one of the factors involved in early fibrosis progression due to recurrent hepatitis C in female recipients.
Notes:
2003
2002
 
PMID 
Daniele Gasparini, Monica Del Forno, Massimo Sponza, Barbara Branca, Pierluigi Toniutto, Andrea Marzio, Mario Pirisi (2002)  Transjugular intrahepatic portosystemic shunt by direct transcaval approach in patients with acute and hyperacute Budd-Chiari syndrome.   Eur J Gastroenterol Hepatol 14: 5. 567-571 May  
Abstract: When Budd-Chiari syndrome (BCS) is due to occlusion of all three hepatic veins, the standard transjugular intrahepatic portosystemic shunt (TIPS) technique can be extremely laborious. A feasible alternative is to use the direct transcaval approach, by which a shunt can be created directly between the intrahepatic inferior vena cava and the portal vein. We describe two patients (one with acute BCS and one with hyperacute BCS) who were successfully managed with this modified technique. Both patients recovered; one of them underwent elective liver transplantation 15 months after the procedure, whereas the other still had good hepatic function and a patent stent 24 months after the procedure. We conclude that, in selected patients with acute and hyperacute BCS, placement of a TIPS by the direct transcaval approach is a rapid and effective emergency procedure, which can either be curative or function as a bridge for elective liver transplantation.
Notes:
2001
 
PMID 
C Fabris, P Toniutto, C A Scott, E Falleti, C Avellini, M Del Forno, M Mattiuzzo, B Branca, M Pirisi (2001)  Serum iron indices as a measure of iron deposits in chronic hepatitis C.   Clin Chim Acta 304: 1-2. 49-55 Feb  
Abstract: Serum iron indices are believed to be elevated in patients with hepatitis C virus (HCV) infection in connection to the presence of hepatic inflammation, though this hypothesis has never been formally tested. We studied 69 consecutive, unselected anti HCV antibody positive patients, aged 14 to 70 years. Iron, transferrin saturation and ferritin were measured in fasting serum samples. Histologically detectable iron (HDI) as well as histologic grading and staging were estimated semiquantitatively in liver biopsy samples. The median values for serum iron, transferrin saturation and serum ferritin were 24 micromol/l (range, 8-61), 29 percent (range, 6-77) and 170 microg/l (range, 1-954), respectively. At univariate analysis, all three serum iron indices were positively correlated with grading and staging scores, as well as with HDI in the liver; only serum iron was positively correlated with transaminases. At multivariate analysis, independent associations were found between serum iron and the grading score; ferritin and sinusoidal and portal HDI; transferrin saturation and total hepatic HDI. In conclusion, in hepatitis C, serum iron reflects the degree of current hepatic inflammation and necrosis, whereas the extent of progressive deposition of iron in sites of fibrosis is best reflected by serum ferritin. Transferrin saturation is the best predictor of the status of hepatic iron deposits.
Notes:
 
PMID 
M Pirisi, C Avellini, C A Scott, P Toniutto, D Intersimone, G Aprile, B Branca, E Fumo (2001)  Recent advances in the pathophysiology, diagnosis and treatment of hereditary hemochromatosis and other iron overload syndromes.   Adv Clin Path 5: 4. 121-131 Oct  
Abstract: Recent years have witnessed tremendous advances in the fields of pathophysiology, diagnosis and management of hereditary hemochromatosis (HH) and other iron overload syndromes, the dreadful consequences of which are fully preventable by early diagnosis and treatment. Missense mutations in HFE, a newly discovered gene encoding for a major histocompatibility class-I like molecule, have been found to be strictly associated with most cases of HH. The mechanisms by which a dysfunctional HFE molecule determines increased absorption of iron in HH are on the way to be fully clarified, due to the availability of a knockout mouse model. Epidemiologic studies have shown that HH is one of the most common human hereditary disorders. The possibility to identify HFE heterozygotes by means of a simple genetic test have prompted studies on the association between HFE mutations and iron overload syndromes different from HH. In the era of the historic completion of the human genome projects, genetic testing for HH may soon qualify for being adopted in universal population screening policies. In the present paper, the recent advances in the fields of genetics and pathophysiology of HH and other iron overload syndromes will be summarized. Furthermore, its clinical features, pathology and treatment will be reviewed, and the emerging issues of cost-effective diagnosis and of possible population screening strategies will be succintly discussed.
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PMID 
M Pirisi, P Toniutto (2001)  Periodic clinical monitoring after liver transplantation   Recenti Prog Med 92: 5. 355-361 May  
Abstract: During the last two decades, owing to advances in immunosuppressive pharmacotherapy, liver transplantation has been increasingly accepted by the medical community as an effective treatment for patients with end-stage liver disease. Successful transplantation of the liver, however, requires frequent monitoring. Most of the serious infectious complications and allograft dysfunction occur during the early post-transplantation period (i.e., first six months). Blood levels of cyclosporine or tacrolimus, the two major calcineurin inhibitors currently in use, need to be frequently checked. Drug dosage is adjusted in order to maintain target serum concentrations and the patients free of side-effects. In the time, the risk of acute allograft rejection decreases considerably, whereas the proportion of patients with fibrosis or cirrhosis increases, particularly among hepatitis C virus carriers. Graft loss may occur, secondary to recurrent disease or chronic rejection. Patients with well-functioning grafts may still be affected by significant comorbidities, such as hypertension, diabetes, obesity, hyperlipidemia and osteoporosis, which appear to be related to long-term immunosuppression. The incidence of lymphoma, skin and colorectal cancers in liver transplantation recipients exceeds those found in the general population and requires early detection. The principles of the management of medical problems after liver transplantation are a careful clinical assessment of the patient and a judicious use of laboratory tests, radiological evaluation and liver biopsy.
Notes:
2000
 
DOI   
PMID 
M Pirisi, C A Scott, C Avellini, P Toniutto, C Fabris, G Soardo, C A Beltrami, E Bartoli (2000)  Iron deposition and progression of disease in chronic hepatitis C. Role of interface hepatitis, portal inflammation, and HFE missense mutations.   Am J Clin Pathol 113: 4. 546-554 Apr  
Abstract: Histologically detectable iron (HDI) and HFE mutations were searched for in liver biopsy specimens from 58 Italian patients with chronic hepatitis C, and morphologic features were compared to examine their reciprocal relation and their contribution to disease progression. HDI was evident in 48% of cases with features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI increased with stage; grade was related to all iron scores because of the contribution of portal inflammation and interface hepatitis. HFE mutations were seen in 47% of patients with chronic hepatitis C and in 28% of control subjects; they were related to stage and the His63Asp mutation to portal HDI. On multivariate analysis, grade but not stage or HFE mutations was associated with HDI in all sites. Interface hepatitis with its sequelae (sinusoidal capillarization and microshunting) represents a major factor in iron deposition in chronic hepatitis C and justifies the features of HDI. HFE mutations are not responsible for HDI deposition but could favor the progression of virus-induced damage independently from interference with iron metabolism.
Notes:
 
PMID 
M Pirisi, C Fabris, S Luisi, M Santuz, P Toniutto, D Vitulli, E Federico, M Del Forno, M Mattiuzzo, B Branca, F Petraglia (2000)  Evaluation of circulating activin-A as a serum marker of hepatocellular carcinoma.   Cancer Detect Prev 24: 2. 150-155  
Abstract: Because in experimental hepatocarcinogenesis apoptosis increases from normal to preneoplastic to carcinoma tissue, proapoptotic factors, such as activin-A, may represent useful markers for hepatocellular carcinoma (HCC). In this study, serum activin-A was measured in 99 cirrhotic patients, of whom 55 had HCC. Activin-A concentrations were higher in HCC patients (median, 2.33 ng/ml; range, 0.41-8.12) than in patients with nonmalignant cirrhosis (1.28 ng/ml; range, 0.35-6.25) (P < .05). All 12 patients with activin-A greater than 3 ng/ml and serum alpha-fetoprotein greater than 30 ng/ml had HCC, in comparison to 32 of 41 patients who had only one and to 11 of 46 patients who had both markers below these cutoffs (P < .0001). No correlation was found between activin-A and alpha-fetoprotein in the two groups, whereas in patients with HCC, activin-A was strictly correlated with serum aspartate aminotransferase (P < .001). Activin-A mRNA for inhibin betaA subunit was expressed both in tumor and nontumor liver tissues in a case of HCC superimposed on cirrhosis and was not expressed in a case of HCC without cirrhosis. In conclusion, cirrhotic patients with HCC have high serum activin-A, to the production of which both the cirrhotic liver and the liver tumor are likely to contribute.
Notes:
 
PMID 
M Pirisi, P Toniutto, A Uzzau, C Fabris, C Avellini, C Scott, L Apollonio, C A Beltrami, F Bresadola (2000)  Carriage of HFE mutations and outcome of surgical resection for hepatocellular carcinoma in cirrhotic patients.   Cancer 89: 2. 297-302 Jul  
Abstract: BACKGROUND: Aggressive hepatocellular carcinoma (HCC) complicates frequently hereditary hemochromatosis, a disease for which a strong candidate gene, named HFE, has recently been identified. Patients with HCC who are heterozygotes for mutations in the HFE gene might have distinct features and a distinct disease course. METHODS: The presence of the 2 mutations associated with hereditary hemochromatosis (C282Y and H63D) was sought by restriction fragment length polymorphism in 61 cirrhotic patients (46 males and 15 females) who underwent resection for HCC at a single institution. RESULTS: There were 4 heterozygotes for the C282Y mutation and 6 homozygotes + 20 heterozygotes for the H63D mutation, with no compound heterozygotes. Carriage of >/= 1 HFE mutated allele was significantly more frequent in HCC patients than in 149 control subjects (44% vs. 29%, P = 0.005). Among C282Y heterozygotes, 3 of 4 were female, compared with 12 of 57 wild-type carriers (P = 0.015); no gender distribution existed among patients carrying H63D alleles (6 of 26 vs. 9 of 35, P = 0.813). Survival was longer for patients with wild-type HFE than for those with mutated HFE (67% vs. 22% at 3 years; hazard ratio = 0.42, 95% confidence interval = 0.21-0.80) (P < 0.01). The negative effect on survival that resulted from possessing >/= 1 HFE mutated allele was maintained even after adjustment for gender, age, presence of tumor capsule, presence of comorbid factors, Okuda stage, Edmonson grading, and number of lesions (P = 0.01). CONCLUSIONS: Testing for HFE mutations may help identify HCC patients with dismal prognoses for whom surgical resection may not represent the best treatment option.
Notes:
1999
 
PMID 
P Toniutto, E Falleti, V Gasparini, C Fabris, S G Tisminetzky, T Lombardelli, P Pacco, A Satta, M Pirisi (1999)  IgM antibody response to the hepatitis C virus core protein in intravenous drug users.   Diagn Microbiol Infect Dis 33: 2. 69-73 Feb  
Abstract: To verify whether a solid-phase enzyme immunoassay for serum IgM antibodies to the hepatitis C virus (HCV) core protein (IgM anti-HCVcore) might be proposed as a surrogate test for serum HCV RNA, we studied 86 anti-HCV antibody-positive intravenous drug users. Serum HCV RNA was demonstrated by RT-PCR with primers derived from the 5' non-coding and the core region. IgM anti-HCVcore antibodies were found in 62/86 (72%) subjects; circulating HCV RNA was detected by the 5' noncoding assay in 53/86 samples (62%) and by the core region assay in 35/86 samples (41%). IgM anti-HCVcore reactivity was associated with core HCV RNA seropositivity (p < 0.05) but not with 5' noncoding HCV RNA seropositivity (p = NS). Patients infected by HCV type 1a were more-often positive for IgM anti-HCVcore (p < 0.05) and for core HCV RNA (p = 0.005) than patients infected by other HCV genotypes. IgM anti-HCVcore reactivity was significantly more common in subjects positive for core HCV RNA (p < 0.005) and in subjects aged > 30 years (p < 0.05). In conclusion, the IgM anti-HCVcore assay frequently tests positive in intravenous drug users, particularly when infected by HCV 1a, but is not a surrogate of testing for serum HCV RNA.
Notes:
 
PMID 
S Brusaferro, F Barbone, P Andrian, G Brianti, L Ciccone, A Furlan, D Gnesutta, S Stel, E Zamparo, P Toniutto, P Ferroni, V Gasparini (1999)  A study on the role of the family and other risk factors in HCV transmission.   Eur J Epidemiol 15: 2. 125-132 Feb  
Abstract: BACKGROUND/AIMS: To understand the intrafamilial transmission and the existing risk factors related to HCV infection in subjects confirmed anti-HCV positive, their sexual partners and household contacts in Friuli, North-East Italy. METHODS: We enrolled all the subjects that were consecutively identified as HCV positive during routine laboratory testing in six health districts and their household contacts. From each subject we obtained a blood sample, demographic data and a medical history including the existence of risk factors for HCV. Antibodies to HCV were detected employing a commercially available second-generation enzyme immunoassay (EIA); positive serum specimens were retested using a second-generation recombinant immunoblot assay (RIBA-2). RESULTS: We recruited 743 subjects, 229 first subjects identified as HCV positive and 514 household contacts. There were no statistically significant differences in positivity among household contacts. Analysing intracouple transmission we found no significant differences by gender in couples both with and without parenteral risk factors. We found, both with univariate and multivariate analysis, as statistically significant risk factors in all the subjects: age older than 60, blood transfusions (particularly those performed before 1984), surgical procedures such as abortion and/or uterine curettage, history of HBV infection, intravenous drug use, and tattooing. CONCLUSIONS: Our results stress the low relevance of sexual transmission in the intrafamilial context, the importance of abortion and/or uterine curettage, the important role of blood transfusions in the past, a higher prevalence of HCV infection within a household of a HCV positive member compared to all other existing data in the area.
Notes:
 
PMID 
P Toniutto, C Fabris, F Barbone, S G Tisminetzky, D Liani, T Galai, G Barillari, F Biffoni, V Gasparini, M Pirisi (1999)  Immunoreactivity to putative B-cell epitopes of hepatitis G virus polyprotein in viremic and nonviremic subjects.   Clin Diagn Lab Immunol 6: 4. 573-576 Jul  
Abstract: The hepatitis G virus (HGV) polyprotein was scanned by computer-aided prediction of antigenicity to search for B-cell epitopes. Four polypeptide sequences, V37D (amino acids [aa] 1685 to 1721), V36S (aa 2102 to 2137), P37R (aa 2156 to 2192), and C40P (aa 2280 to 2319), were identified and synthesized for use in immunoassays. Antibodies to these peptides were searched for in a panel of 239 serum samples, which were also tested for anti-E2 antibodies and HGV RNA. Furthermore, the course of HGV markers was studied prospectively in four patients who had been transfused with HGV RNA-positive blood. There was a negative association between immunoreactivity to V37D and P37R and presence of HGV RNA (2 of 53 and 1 of 53, respectively; P < 0.05); none of the subjects with dual antibody positivity was HGV RNA positive. Anti-V37D and anti-P37R antibodies compared favorably with anti-E2 antibodies as markers of recovery from HGV infection. These results might be useful for the development of new, more sensitive diagnostic assays.
Notes:
 
PMID 
C Fabris, M Del Forno, E Falleti, P Toniutto, M Pirisi (1999)  Kinetics of serum soluble tumour necrosis factor receptor (TNF-R) type-I and type-II after a single interferon-alpha (IFN-alpha) injection in chronic hepatitis C.   Clin Exp Immunol 117: 3. 556-560 Sep  
Abstract: Circulating soluble TNF receptors, which act as TNF inhibitors, increase following the administration of IFN-alpha. Whether this is due to a direct IFN action or to indirect mechanisms involving the release of other cytokines is unclear. The kinetics of serum IFN, TNF, IL-6, IL-10, soluble TNF receptor type-I (sTNF-RI) and sTNF-RII were evaluated by enzyme immunoassays in 11 patients with chronic hepatitis C, following the first dose of recombinant human IFN-alpha2b (3 MU given subcutaneously). sTNF-RI concentrations paralleled IFN concentrations, rising from a mean +/- s.e.m. value of 3.5 +/- 0.3 ng/ml at baseline to a peak value of 5.5 +/- 0.5 ng/ml after 9 h, followed by a return to 4.1 +/- 0.4 ng/ml after 24 h (P = 0.0001). sTNF-RII concentrations, which were 7.6 +/- 0.5 ng/ml at baseline, fell initially to 6.9 +/- 0.5 ng/ml, to reach a peak at 24 h of 9.0 +/- 0.7 ng/ml (P < 0.0001). In contrast, the concentrations of TNF, IL-6 and IL-10 fluctuated with no significant changes at any time point. The area under the curve (AUC) of incremental IFN values had a strong positive correlation with the AUC of incremental sTNF-RI values (r = 0.75, P < 0.01). In patients with hepatitis C, IFN concentrations reached after a single dose of IFN were paralleled by correlationally increased concentrations of sTNF-RI, which are a much better marker of administered IFN than sTNF-RII, IL-6 or IL-10.
Notes:
1998
 
PMID 
P Toniutto, M Pirisi, C Fabris, P Bardus, G Soardo, D Vitulli, S G Tisminetzky, P Pacco, V Gasparini, F Baralle, E Bartoli (1998)  High prevalence of infection with hepatitis G virus in patients with hepatic and extrahepatic malignancies.   J Hepatol 28: 4. 550-555 Apr  
Abstract: BACKGROUND/AIMS: The pathogenic role of hepatitis G virus, the recently discovered blood-borne agent, is controversial. Our aim was to ascertain the prevalence of hepatitis G virus infection in hepatic and in extrahepatic malignancies. METHODS: We studied 166 Italian patients (112 male, 54 female, mean age 61.8+/-9.3, mean+/-SD, range 34-85). One hundred and eighteen had cirrhosis, which was complicated by hepatocellular carcinoma in 66 cases. Forty-eight patients had extra-hepatic malignancies. Circulating HGV RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) of both the nonstructural-3 and 5'noncoding regions of the hepatitis G virus genome. Antibodies to the E2 protein of hepatitis G virus were detected by means of an enzyme-linked immunosorbent assay. RESULTS: Ongoing HGV infection was detected in 30/66 (46%) patients with hepatocellular carcinoma, 12/52 (23%) patients with cirrhosis, and 14/48 (29%) patients with extrahepatic malignancies (p<0.05). Evidence of exposure to hepatitis G virus (detection of either HGV RNA or anti-E2 antibodies) was found in 46% of patients with cirrhosis, 66% of patients with hepatocellular carcinoma, and 39% of patients with extrahepatic malignancies. Serum HGV RNA positivity was associated with a hematocrit value < or = 0.35 and with history of exposure to blood products (p<0.005). CONCLUSIONS: Ongoing hepatitis G virus infection is detected at a very high rate in patients with hepatocellular carcinoma, but is also fairly common in extrahepatic malignancies. Hepatitis G virus infection in these patients is likely to originate from exposure to blood products, and to persist because of deficient immune surveillance.
Notes:
 
PMID 
C Fabris, G Soardo, E Falleti, P Toniutto, D Vitulli, E Federico, M Del Forno, M Mattiuzzo, F Gonano, M Pirisi (1998)  Relationship among hepatic inflammatory changes, circulating levels of cytokines, and response to IFN-alpha in chronic hepatitis C.   J Interferon Cytokine Res 18: 9. 705-709 Sep  
Abstract: To investigate the relationship among circulating cytokines, inflammation in the liver, and kind of response to interferon-alpha (IFN-alpha) in hepatitis C, we studied 63 consecutive patients (38 male, 25 female), treated with IFN for up to 1 year. Serum tumor necrosis factor-alpha (TNF-alpha) was measured at baseline and after 3 months of treatment. Transient (TR) or sustained response (SR) was observed in 29 and 16 patients, respectively. Baseline levels of TNF < or = 22 ng/L were observed in 69% of patients with SR, 55% of patients with TR, and 22% of nonresponders (p < 0.01). There was a significant correlation between baseline TNF levels and histologic grading score of hepatitis (p < 0.01). After 3 months of treatment, TNF levels >22 ng/L were observed in 63% of patients with SR, 69% of patients with TR, and 83% of nonresponders (p NS). Independent of the treatment outcome, TNF levels were lower at baseline and increased significantly with treatment in patients with lower histologic grading (p < 0.005). In conclusion, in patients with chronic hepatitis C, circulating TNF levels correlate with the degree of inflammation in the liver. Response to IFN is accompanied by an inflammatory response involving the release of TNF.
Notes:
 
PMID 
M Pirisi, P Toniutto, C Fabris, T Lombardelli, E Falleti, S G Tisminetzky, F Baralle, E Bartoli (1998)  Factors associated with serum HCV RNA positivity in anti-HCV antibody positive intravenous drug users.   J Clin Epidemiol 51: 5. 423-427 May  
Abstract: Serum hepatitis C virus (HCV) RNA, HCV genotypes and liver function tests were evaluated in a series of 189 unselected, consecutive anti-HCV positive intravenous drug users (IVDUs). Serum HCV RNA was detected in 106/189 patients. Abnormal liver function tests were associated with alcohol abuse, but not with the presence of serum HCV RNA. Among 109 patients retested after a mean follow-up of 21 months, 41 were intermittently serum HCV RNA positive. Patients persistently negative had more commonly a past history of acute hepatitis. A history of prostitution and/or a pattern of abuse involving >30 injections per week were related to infection by genotype 3a. In conclusion, serum HCV RNA is either transiently or persistently detectable in most anti-HCV positive IVDUs, but bears no association with abnormal liver biochemistry. Infection by HCV-3a is more common in IVDUs with more deviant life styles. In those cases where serum HCV RNA is found repeatedly negative, HCV infection may have been cleared, possibly through an episode of acute hepatitis.
Notes:
1997
 
PMID 
C Fabris, E Falleti, E Federico, P Toniutto, M Pirisi (1997)  A comparison of four serum markers of fibrosis in the diagnosis of cirrhosis.   Ann Clin Biochem 34 ( Pt 2): 151-155 Mar  
Abstract: C-terminal peptide of procollagen I, N-terminal peptide of procollagen III, collagen IV and serum prolyl hydroxylase were measured in 100 patients with cirrhosis and 71 patients with noncirrhotic chronic liver disease. Patients with cirrhosis had significantly higher mean values of prolyl hydroxylase, collagen IV, N-terminal peptide of procollagen III and C-terminal peptide of procollagen I as compared to noncirrhotic patients. This difference was maintained for collagen products even after stratification for alcohol intake, although all markers of fibrosis were higher in alcoholics. Stepwise logistic regression analysis showed that collagen IV, and N-terminal peptide of procollagen III were independently associated with cirrhosis. Receiver-operating characteristic (ROC) curves showed that collagen IV and N-terminal peptide of procollagen III perform more efficiently than C-terminal peptide of procollagen I and prolyl hydroxylase in identifying cirrhosis.
Notes:
 
PMID 
M Pirisi, C Fabris, P Toniutto, E Falleti, S G Tisminetzky, M Gerotto, G Soardo, D Vitulli, M Del Forno, F Baralle, E Bartoli (1997)  Endogenous interferon-alpha concentration and outcome of interferon treatment in patients with chronic hepatitis C.   Dig Dis Sci 42: 4. 767-771 Apr  
Abstract: To verify its value with regard to the outcome of therapy in chronic hepatitis C, serum interferon-alpha (IFN) was measured by ELISA in 70 patients (43 male, 27 female) with chronic hepatitis C, treated with IFN 9 MU/week subcutaneously for up to one year. Serum IFN was detectable in 49/70 patients, 16 of whom had IFN values >125 pg/ml. Only 1/22 patients who maintained a sustained response six months after the end of treatment had pretreatment serum IFN > 125 pg/ml, in comparison to 15/48 patients who did not respond or who relapsed (chi2 6.1, P < 0.02). At multivariate analysis the predictive value of serum IFN was independent of age, sex, presence of cirrhosis, infection by genotype 1b (improvement chi2 7.1, P < 0.01). In patients with chronic hepatitis C, measurement of serum IFN at baseline might be useful for the selection of patients with higher probability of long-term response.
Notes:
1996
 
PMID 
C Fabris, M Pirisi, G Soardo, P Toniutto, E Falleti, D Vitulli, F Pezzetta, F Gonano, E Bartoli (1996)  Diagnostic usefulness of acute-phase protein measurement in hepatocellular carcinoma.   Cancer Invest 14: 2. 103-108  
Abstract: To compare the diagnostic usefulness as markers of hepatocellular carcinoma (HCC) of alpha1-antitrypsin, C-reactive protein, and alpha1-acid glycoprotein (all determined by nephelometric methods), we studied 132 subjects (74 male, 58 female): 43 had mild chronic liver disease, 32 cirrhosis, 24 HCC; 33 were controls. A total of 29.2% of the patients with HCC had alpha1-acid glycoprotein > 100 mg/dl, 75.0% had alpha1-antitrypsin > 220 mg/dl, 70.8% had C-reactive protein > 5 mg/L. In cirrhotics, frequencies were 3.1, 50.0 and 59.4%, respectively; in patients with mild chronic liver disease, 14.0, 11.6, and 32.6% (chi2 12.3, p < 0.01; chi2 47.3, p < 0.0001; chi2 38.0, p < 0.0001, respectively). alpha1-fetoprotein performed better than all acute-phase proteins. We conclude that, due to their low specificity and/or sensitivity, none of the three acute-phase reactants tested can be recommended for diagnostic use as biological markers of HCC in Western patients.
Notes:
 
PMID 
M Pirisi, C Fabris, G Soardo, P Toniutto, D Vitulli, E Bartoli (1996)  Prognostic value of serum alpha-1-antitrypsin in hepatocellular carcinoma.   Eur J Cancer 32A: 2. 221-225 Feb  
Abstract: To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female, mean age +/- SD 63.0 +/- 9.3 years) in whom hepatocellular carcinoma developed with pre-existing cirrhosis. Median survival time was 245 days (range 4-1568+). 30 patients had serum A1AT concentration of < or = 2.20 g/l (Group A) while 45 (Group B) had alpha-1-antitrypsin > 2.20 g/l. Median survival was 518 days in Group A and 81 days in Group B (Mantel-Cox 20.95, P < 0.0001; hazard ratio 0.26, 95% confidence limits 0.15-0.46). By stepwise survival analysis, alpha-1-antitrypsin together with bilirubin, tumour size and blood urea nitrogen were chosen among 17 variables as the only independent predictors of survival. We conclude that measurement of serum A1AT concentration might be useful as an inexpensive, widely available prognostic marker of hepatocellular carcinoma.
Notes:
 
PMID 
E Falleti, C Fabris, M Pirisi, G Soardo, D Vitulli, P Toniutto, E Bartoli, N Bortolotti, F Gonano (1996)  Circulating intercellular adhesion molecule 1 predicts non-specific elevation of alpha 1-fetoprotein.   J Cancer Res Clin Oncol 122: 6. 366-369  
Abstract: Molecules governing cellular interactions have been suggested to be involved in the spurious elevation of alpha 1-fetoprotein (AFP) in non-neoplastic liver disease. To explore this controversial issue, we measured AFP, circulating intercellular adhesion molecule 1 (cICAM-1), and common liver function tests in 111 patients (71 male, 40 female). Eighty-four patients had non-neoplastic chronic liver disease and 27 had hepatocellular carcinoma. The concentration of cICAM-1 was determined immunoenzymatically. In patients with non-neoplastic chronic liver disease, univariate analysis demonstrated a significant correlation between AFP and cholinesterase (R = -0.397, P < 0.001), aspartate aminotransferase (R = 0.421, P < 0.001), bilirubin (R = 0.231, P < 0.05) and cICAM-1 (R = 0.430, P < 0.001). Multivariate analysis among these variables and AFP indicated cICAM-1 to be the strongest independent predictor of AFP. We conclude that cICAM-1 compares favourably with liver function tests in predicting non-specific AFP variations in non-neoplastic chronic liver disease, suggesting a link between targeting of the inflammatory damage to the hepatocyte and development of neoplasia.
Notes:
 
PMID 
P Toniutto, M Pirisi, S G Tisminetzky, C Fabris, E Chinellato, M Gerotto, E Falleti, P Ferroni, T Lombardelli, E Bartoli, F Baralle (1996)  Discordant results from hepatitis C virus genotyping by procedures based on amplification of different genomic regions.   J Clin Microbiol 34: 10. 2382-2385 Oct  
Abstract: We compared the results of genotyping hepatitis C virus (HCV) either by PCR amplification of the core region or by hybridization of PCR-amplified products of the 5' untranslated region (5'UTR assay). Serum samples from 144 Italian anti-HCV-positive patients (106 drug abusers and 38 patients with chronic viral liver disease but no history of drug abuse) were studied. The original core region assay described by Okamoto et al. (H. Y. Okamoto, Y. Sugiyama, S. Okada, K. Kurai, Y. Akahane, Y. Sugai, T. Tanaka, K. Sato, F. Tsuda, Y. Miyakawa, and M. Mayumi, J. Gen. Virol. 73:673-679, 1992) allowed genotyping of 75 of 144 samples. A modified version of Widell et al. (A. Widell, S. Shev, S. Månsson, Y.-Y. Zhang, U. Foberg, G. Norkrans, A. Frydén, O. Weiland, J. Kurkus, and E. Nordenfelt, J. Med. Virol. 44:272-279, 1994) allowed genotyping of 11 of 79 samples (50 of 79 samples remained unclassified by the method of Okamoto et al. In contrast, all 144 samples were genotyped by the 5'UTR assay. Forty-six of 75 (61 percent) of the samples genotyped by the method of Okamoto et al. and 10 of 11 (91 percent) of the samples genotyped by the method of Widell et al. had results consistent with those obtained by the 5'UTR assay. According to the results of direct sequencing, the method of Okamoto et al. erroneously classified seven samples as having mixed infections. In conclusion, HCV genotyping seems more reliable when it is performed by the 5'UTR assay than by either of two core region assays. The major advantage provided by the 5'UTR assay is a much lower proportion of negative or indeterminate results in younger patients with histories of drug abuse or infection by genotypes other than HCV type 1.
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PMID 
M Pirisi, C Fabris, E Falleti, G Soardo, P Toniutto, D Vitulli, F Gonano, E Bartoli (1996)  Serum soluble vascular-cell adhesion molecule-1 (VCAM-1) in patients with acute and chronic liver diseases.   Dis Markers 13: 1. 11-17 Aug  
Abstract: Our aim was to ascertain the degree of variation of serum soluble vascular cell adhesion molecule-1 (VCAM-1) concentrations according to the nature and the severity of an underlying liver disease. One-hundred forty sera collected from 123 patients (83 male, 40 female) with acute hepatitis (n = 14), mild chronic liver disease (n = 52) or cirrhosis (n = 57) of different etiologies as well as from 17 healthy blood donors (8 male, 9 female) were studied. Soluble VCAM-1 concentration was measured immunoenzymatically. One-way analysis of variance revealed a significant variability of the mean values of soluble VCAM-1 among groups (F = 80.02, p < 0.0001). All groups of patients had higher soluble VCAM-1 than controls; moreover, patients with acute hepatitis and patients with cirrhosis had higher soluble VCAM-1 levels than patients with mild chronic liver disease (Bonferroni's test, p < 0.01). These results did not change after stratification of patients according to the etiology (viral or toxic) of liver disease (two-way analysis of variance: grouping factor diagnosis, F = 60.39, p < 0.0001; grouping factor etiology, F = 1.73, p NS). Cholinesterase, total bilirubin, circulating thrombocytes and blood area nitrogen were the independent predictors of the concentration of soluble VCAM-1. In conclusion, patients with liver disease have high serum soluble VCAM-1, which seems to reflect more the severity of impairment of liver function rather than the etiologic nature of the disease.
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1995
 
PMID 
M Pirisi, P Ferroni, C Fabris, P Toniutto, G Soardo, D Vitulli, V Gasparini, E Bartoli (1995)  Anti-envelope antibodies in anti-hepatitis C virus (HCV) positive patients with and without liver disease.   Infection 23: 1. 24-28 Jan/Feb  
Abstract: Our aim was to verify whether the presence of antibodies to HCV envelope protein might mark the occurrence of liver damage, as recently suggested in the literature. Sera from 104 patients (62 male, 42 female) were tested: 84 were positive and 20 were negative to a second generation enzyme immunoassay for anti-HCV antibodies; 51 patients had mild chronic liver disease (44 chronic hepatitis, seven steatosis), 43 had liver cirrhosis (superimposed by hepatocellular carcinoma in 18) and ten were asymptomatic anti-HCV positive subjects with normal liver function tests. Besides, all sera were tested by means of an enzyme immunoassay for the presence of serum antibodies to the synthetic peptide S24A (SIYPGHVSGH RMAWDMMMNW SPTA) derived from amino acids 307-330 of HCV polyprotein. Anti-S24A antibodies were detected in 40/84 sera positive and 1/20 negative at anti-HCV testing (Pearson chi 2 12.29; p = 0.005). Among anti-HCV positive sera, no significant difference existed in anti-S24A status with regard to clinical evidence of liver disease, ALT concentration or HCV RNA positivity. Thus, anti-S24A antibodies are detectable in approximately half of HCV-positive sera, but they do not seem to add significant clinical information to existing tests or to be useful as putative markers of viraemia.
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PMID 
M Pirisi, C Fabris, P Toniutto, D Vitulli, G Soardo, E Falleti, F Gonano, P Ferroni, V Gasparini, E Bartoli (1995)  Reactivity to B cell epitopes within hepatitis C virus core protein and hepatocellular carcinoma.   Cancer Res 55: 1. 111-114 Jan  
Abstract: Our aim was to investigate the existence of an association between B cell responsiveness to hepatitis C virus (HCV) core protein and progression of liver disease. In fact, the persistence of HCV infection is permitted by avoidance of viral clearance, despite chronic inflammation in the liver; this process ends with the development of hepatocellular carcinoma in many patients. On the basis of computerized prediction of antigenicity of the genomic sequence of HCV core protein, three 15-mer peptides (named Q15V, R15P, and G15V) were synthesized to be used as antigens in an enzyme immunoassay. Sera from 97 patients (65 males and 32 females) were tested: 43 patients had mild chronic liver disease (steatofibrosis, chronic persistent, or chronic active hepatitis) and 54 had cirrhosis, which was complicated by hepatocellular carcinoma (HCC) in 19. Seventy-six patients were positive to anti-HCV testing by second generation ELISA and 21 were negative. Rates of positivity for synthetic peptides in anti-HCV-positive versus anti-HCV negative patients were as follows: 53 of 76 and 0 of 21 for anti-Q15V; 41 of 76 and 0 of 21 for R15P; and 67 of 76 and 2 of 21 for G15V. Rates of positivity to anti-Q15V and anti-G15V were similar among diagnostic groups (Pearson's chi 2, 1.97, P > 0.10 and 0.45, P > 0.10), whereas anti-R15P antibodies were detected at a significantly lower rate in patients with HCC (2/13) in comparison to mild chronic liver disease (22/35) and cirrhosis (17/28) (Pearson's chi 2, 9.42, P < 0.01). We conclude that anti-R15P antibodies are uncommon in anti-HCV-positive patients with HCC. During the course of chronic HCV infection, anti-R15P testing might help to identify a subgroup at higher risk to develop HCC.
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PMID 
M Pirisi, C Fabris, G Soardo, E Falleti, D Gasparini, D Vitulli, P Toniutto, F Gonano, E Bartoli (1995)  Hepatic release of erythropoietin induced by transarterial chemoembolization in patients with hepatocellular carcinoma.   Hepatology 22: 1. 148-152 Jul  
Abstract: It has been shown previously that erythropoietin expression in vitro by hepatoma cells increases in response to hypoxia. To verify whether hypoxia of the tumor might result in hepatic release of erythropoietin in vivo, serum erythropoietin concentrations were measured immunoenzymatically in 12 patients (5 women, 7 men) who underwent transarterial chemoembolization for hepatocellular carcinoma. Peripheral blood samples were collected at baseline, and after 6 hours and 1, 2, 3, and 7 days after the procedure. In a second set of experiments, performed in three male patients also undergoing chemoembolization for hepatocellular carcinoma, paired blood samples were collected after catheterization of the hepatic veins and of the right antecubital vein. None of the patients had erythrocytosis. In comparison with a baseline mean value +/- SEM of 100.6 +/- 12.6 micrograms/L, serum erythropoietin concentrations were the following; +6 hours, 55.4 +/- 18.0 (P < .001); +1 day, 102.4 +/- 24.7 (P = NS), +2 days, 183.0 +/- 31.1 (P < .05); +3 days, 155.0 +/- 26.0 (P < .05); +7 days, 153.3 +/- 27.4 (P < .05) (matched Student's t-test). The ratio of hepatic vein/antecubital vein serum erythropoietin concentrations increased from 0.85 at baseline to 1.30 at +2 days, paralleling the increase of aspartate transaminase (r = .914, P < .005). After chemoembolization, no correlation was found between serum erythropoietin and alpha-1-fetoprotein concentrations. The concentration of the latter, stable initially, decreased 7 days after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID 
M Pirisi, C Fabris, A Ceriello, G Soardo, R Giacomello, P Toniutto, D Vitulli, F Gonano, E Bartoli (1995)  Deficient antithrombin III activity and enhanced fibrinolysis in patients with liver disease: evidence against a cause-effect relationship.   Acta Gastroenterol Belg 58: 2. 230-237 Mar/Apr  
Abstract: To investigate the pathogenesis of fibrinolysis in liver disease, antithrombin III (AT III) activity, prothrombin fragment (F1 + 2) and d-dimer (D-DI) were measured in 50 patients with liver disease and in 17 healthy controls. Moreover, 4 patients with cirrhosis were randomly assigned to receive either an intravenous infusion of AT III (at two different dosages) or placebo, with a crossover design. Increased levels of D-DI were detected in patients with cirrhosis and hepatocellular carcinoma in comparison both with control subjects and with patients with acute hepatitis or mild chronic liver disease. An inverse correlation was observed between AT III and D-DI (r = -0.755, P < 0.001, simple linear regression), while no correlation was found between D-DI or AT III and F1 + 2. The correlation of the deficiency of AT III activity by infusion of human AT III did not result in any significant change (P0.10, analysis of variance for repeated measures) of the plasma concentration of either D-DI or F1 + 2, in comparison to placebo. Thus, advanced forms of chronic liver disease, but not acute hepatitis and mild forms of chronic liver disease, are associated with increased plasma concentrations of markers of fibrinolysis, which are inversely correlated with AT III activity. However, the correction of the deficient AT III activity does not affect the plasma concentration of either D-DI or F1 + 2, thence not supporting the hypothesis that enhanced fibrinolysis in advanced liver disease is the result of low-grade disseminated intravascular coagulation.
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PMID 
C Fabris, E Falleti, M Pirisi, G Soardo, P Toniutto, D Vitulli, N Bortolotti, F Gonano, E Bartoli (1995)  Non-specific increase of serum carbohydrate antigen 19-9 in patients with liver disease associated with increased circulating levels of adhesion molecules.   Clin Chim Acta 243: 1. 25-33 Dec  
Abstract: Sialyl-Lewisa antigen (SLe(a)), the immune determinant of carbohydrate antigen 19-9 (CA 19-9), is the ligand of E-selectin. To verify the possibility of an association between nonspecific elevation of CA 19-9 and adhesion molecules, sera from 12 patients with acute hepatitis, 55 with non-cirrhotic chronic liver disease, 33 with cirrhosis and 25 with hepatocellular carcinoma, were tested for common liver function tests. Besides, CA 19-9 and soluble forms of E-selectin, VCAM-1 and ICAM-1 were measured immunoenzymatically. One-way analysis of variance demonstrated that mean CA 19-9 concentration differed among groups (F 15.27, P < 0.0001) with the highest values found in patients with acute hepatitis. By univariate analysis, the strongest correlation of CA 19-9 was with soluble ICAM-1, which by stepwise multiple regression analysis was the only independent predictor of elevated CA 19-9 (multiple R 0.560). The association between ICAM-1 and CA 19-9 might originate in the biliary cells where they might be simultaneously overexpressed during inflammatory processes.
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PMID 
G Soardo, M Pirisi, M Fonda, C Fabris, E Falleti, P Toniutto, D Vitulli, L Cattin, F Gonano, E Bartoli (1995)  Changes in blood lipid composition and response to interferon treatment in chronic hepatitis C.   J Interferon Cytokine Res 15: 8. 705-712 Aug  
Abstract: To assess whether the initial status of lipid metabolism in patients with chronic viral hepatitis might correlate with outcome of therapy, 52 patients (32 males and 20 female) with chronic hepatitis C were studied: 44 were treated with human recombinant interferon-alpha 2b (3 MU three times per week for up to 12 months), and 8 served as controls. At baseline, sera were tested for total and HDL cholesterol, HDL2, HDL3, apolipoprotein A-I, apolipoprotein B, interferon-alpha, tumor necrosis factor, and interleukin-6. Changes in blood lipids were evaluated after 3, 30, and 90 days of treatment. HDL cholesterol, apolipoprotein A-I, and HDL3 decreased by 9.4-11.4% within 4 weeks of starting interferon treatment, but this effect was sustained only in patients with a primary response to interferon. On multivariate analysis, a primary response to interferon correlated with higher apolipoprotein A-I and lower (< 2.23 pg/ml) interleukin-6 levels (p < 0.005 for both). In contrast, a sustained response was significantly more common in patients with low (< or = 13.3 pg/ml) serum interferon-alpha and lower interleukin-6 at baseline but did not correlate with any of the blood lipids. Thus, in chronic hepatitis C, interferon treatment induces specific changes in blood lipids. The concentration of apolipoprotein A-I at baseline is a strong predictor of primary response to treatment, and the likelihood of sustained response seems to be reflected by lower cytokine activation.
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1994
 
PMID 
C Fabris, M Pirisi, G Soardo, E Falleti, F Pezzetta, D Vitulli, P Toniutto, N Bortolotti, F Gonano, E Bartoli (1994)  Value of serum C-reactive protein measurement in the detection of hepatocellular carcinoma superimposed on liver cirrhosis.   J Cancer Res Clin Oncol 120: 4. 229-232  
Abstract: We investigated whether, in Italian patients, C-reactive protein (CRP) determination could be considered a useful adjunct, complementary to alpha 1-fetoprotein, in the detection of liver cancer. CRP was determined by particle-enhanced nephelometry in 171 subjects (102 male, 69 female). Fifty-five patients had mild chronic liver disease (CLD), 45 cirrhosis (CIR), 38 hepatocellular carcinoma (HCC); 33 subjects were healthy controls. Patients with HCC and CIR had higher CRP levels (P < 0.05) than those found in patients with CLD and controls. CRP higher than 5 mg/l was found in 30/38 (78.9%) patients with HCC, 28/45 (62.2%) patients with CIR, 16/55 (29.1%) patients with CLD (chi 2 56.0, P < 0.0001). Sensitivity, specificity and diagnostic accuracy of CRP in diagnosing HCC with respect to CLD+CIR were: 78.9%, 56.0% and 34.9%. However, when considered only in the subgroup of patients with alpha 1-fetoprotein below or equalling 30 ng/ml, they were 50.0%, 54.3% and 4.3% respectively. In conclusion, CRP concentration is frequently elevated in patients with HCC, however, it does not seem to improve the ability of alpha 1-fetoprotein to discriminate HCC from CIR.
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PMID 
M Pirisi, C Fabris, G Soardo, E Cecchin, P Toniutto, E Bartoli (1994)  Thrombocytopenia of chronic liver disease corrected by erythropoietin treatment.   J Hepatol 21: 3. 376-380 Sep  
Abstract: To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count < or = 85,000/microliters were studied. Either a short-term course (7-20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to > or = 100,000/microliters or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70,000 +/- 11,184 to 101,250 +/- 37,625/microliters), while no difference was noted in the placebo group (70,714 +/- 9928 vs 70,000 +/- 10,231/microliters). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Student's t-test, t = -3.80, p < 0.005) and to the results of treatment in the placebo group (unpaired Student's t-test, t = 2.71, p < 0.02). Eight out of 12 recombinant human erythropoietin-treated patients (66%) reached > or = 100,000/microliters platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58,500 +/- 7937 vs 75,750 +/- 7498/microliters, t = -3.69, p = 0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson chi 2 = 4.687, p = 0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID 
M Pirisi, C Scott, C Fabris, G Ferraccioli, G Soardo, R Ricci, P Toniutto, C Avellini, D Vitulli, A M Miotti (1994)  Mild sialoadenitis: a common finding in patients with hepatitis C virus infection.   Scand J Gastroenterol 29: 10. 940-942 Oct  
Abstract: BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease of presumed viral origin; sialoadenitis has been reported to occur in hepatitis C virus (HCV) infection. METHODS: Lip biopsy specimens were graded in 32 consecutive patients with either HCV-related chronic liver disease or SS. RESULTS: Seventeen of 22 HCV-positive patients had sialoadenitis, although generally mild (15 of 17, grades I-II). Severe inflammation (grades III-IV) was observed in 8 of 10 patients with SS (chi-square = 12.6; P < 0.0005). Moreover, HCV-positive patients with sialoadenitis differed from patients with SS in female sex prevalence (6 of 17 versus 10 of 10; chi-square = 10.9; P = 0.0001) and presence of serum antinuclear autoantibodies (0 of 17 versus 9 of 10; chi-square = 23.0; P < 0.0001). Five of 13 HCV-positive patients and 7 of 8 patients with SS were HLA-DR3-positive (chi-square = 4.9; P < 0.05). CONCLUSIONS: Sialoadenitis of HCV-related liver disease is common but differs from SS with regard to predisposing genetic factors, expression of autoimmune markers, and histopathologic severity.
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PMID 
M Pirisi, E Falleti, C Fabris, G Soardo, P Toniutto, D Vitulli, F Pezzetta, N Bortolotti, F Gonano, E Bartoli (1994)  Circulating intercellular adhesion molecule-1 (cICAM-1) concentration in liver disease. Relationship with cholestasis and functioning hepatic mass.   Am J Clin Pathol 102: 5. 600-604 Nov  
Abstract: The authors measured immunoenzymatically circulating intercellular adhesion molecule-1 (cICAM-1) concentration in 135 patients with liver disease of either viral or toxic etiology: 13 had acute hepatitis; 58 had mild chronic liver disease; and 64 had cirrhosis (superimposed in 30 by hepatocellular carcinoma). Forty patients with extrahepatic diseases (19 with malignancies) and 28 healthy blood donors were tested as controls. One-way analysis of variance demonstrated a significant variability of cICAM-1 concentration among groups (F = 76.67, P < .0001), the highest value being recorded in acute hepatitis (Bonferroni's test for pairwise comparisons, P < .01). Total bilirubin showed a strong correlation with cICAM-1 (R = 0.766, P < .001). By stepwise multiple regression analysis the independent predictors of cICAM-1 concentration were chosen in the following order: total bilirubin; aspartate aminotransferase; cholinesterase; alpha-1-antitrypsin; and immunoglobulins. Thus, in addition to inflammation, cholestasis and decline of functioning hepatic mass may influence cICAM-1 concentration.
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1993
 
PMID 
C Fabris, M Pirisi, M P Panozzo, G Soardo, P Toniutto, V Hocza, E Bartoli (1993)  Intensity of inflammatory damage and serum lipid peroxide concentrations in liver disease.   J Clin Pathol 46: 4. 364-367 Apr  
Abstract: AIMS--To investigate variations in serum lipid peroxide activities in relation to various clinical entities of liver disease. METHODS--Serum lipid peroxides were measured fluorometrically in eight patients with acute hepatitis, six with liver steatofibrosis, five with chronic persistent hepatitis, 15 with chronic active hepatitis, 28 with liver cirrhosis, 22 with hepatocellular carcinoma; 19 patients with extrahepatic disease (six malignant, 13 benign) were used as controls. RESULTS--Higher serum lipid peroxide concentrations were found in patients with acute hepatitis (4.52 (SEM 0.56)) nmol/ml than in all other groups of patients (p < 0.01). No significant difference was found among the mean values detected in the groups of patients affected by chronic liver disease and extrahepatic diseases. A history of chronic alcohol consumption was not associated with higher lipid peroxide concentrations. A significant correlation (R2 = 0.4538, R = 0.6737, F = 7.617, p = 0.0000) was found between serum lipid peroxides and a set of indices of inflammation (ESR, total leucocyte count, C-reactive protein) and of hepatic function (aspartate aminotransferase (AST) or alkaline phosphatase (ALP) or bilirubin). Of these, bilirubin was the most significant indicator of inflammation. Analysis of covariance showed a significant difference in lipid peroxide values among groups, even when bilirubin was chosen as an independent variable. CONCLUSIONS--Raised serum lipid peroxide concentrations can be found during acute inflammatory liver disease. Acute change in liver function, reflected by high bilirubin concentrations, seems to be more important for intravascular liberation of lipid peroxides than existence of specific aetiological factors or of severe longstanding global liver damage.
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PMID 
E Falleti, M Pirisi, C Fabris, N Bortolotti, G Soardo, P Toniutto, F Gonano, E Bartoli (1993)  Increase of serum alpha 1-acid glycoprotein despite the decline of liver synthetic function in cirrhotics with hepatocellular carcinoma.   Eur J Clin Chem Clin Biochem 31: 7. 407-411 Jul  
Abstract: alpha 1-Acid glycoprotein, an acute phase reactant synthesised by the liver, has been reported to be increased in neoplastic conditions and reduced in chronic liver disease. We measured serum alpha 1-acid glycoprotein by a nephelometric method in 186 subjects (112 males, 74 females): 55 had mild chronic liver disease (chronic hepatitis and steatofibrosis), 45 cirrhosis, 38 hepatocellular carcinoma, 15 extra-hepatic malignant disease; 33 healthy subjects were used as controls. Analysis of variance demonstrated a significant variability among groups (F = 17.08, P = 0.0000). Higher concentrations of alpha 1-acid glycoprotein were detected in malignant extra-hepatic disease than in all other groups (P < 0.01); concentrations of alpha 1-acid glycoprotein were higher in hepatocellular carcinoma than in cirrhosis (P < 0.01). Multiple regression analysis by groups (dependent variable = alpha 1-acid glycoprotein; group 1 = mild chronic liver disease + cirrhosis; group 2 = hepatocellular carcinoma) showed a significant correlation for both group 1 (r = 0.6264, F = 8.005, P = 0.0000) and group 2 (r = 0.8947, F = 13.643, P = 0.0000). The significant standardised regression coefficients were: cholinesterase, C-reactive protein, gamma-glutamyltransferase and iron (negative) for regression upon group 1; C-reactive protein, alpha 1-antiproteinase, gamma-glutamyltransferase, iron (negative) for regression upon group 2. A difference between the 2 regression equation coefficients was detected (F = 5.209, P = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID 
M Pirisi, C Fabris, E Falleti, G Soardo, P Toniutto, F Gonano, E Bartoli (1993)  Evidence for a multifactorial control of serum erythropoietin concentration in liver disease.   Clin Chim Acta 219: 1-2. 47-55 Oct  
Abstract: We measured serum erythropoietin (EPO) immunoenzymatically in 245 subjects (151 male, 94 female) to investigate the pathophysiology of its liberation in patients with liver disease. Twelve patients had acute hepatitis, 60 mild chronic liver disease (CLD), 50 cirrhosis (CIR), 43 hepatocellular carcinoma (HCC), 16 malignant extrahepatic disease, 32 benign extrahepatic disease (BEN); 32 subjects served as healthy controls. Higher EPO levels were found in all groups of patients as compared with controls (Bonferroni's test, P < 0.01); CIR and HCC had higher values than CLD and BEN (P < 0.01). By multiple regression analysis, EPO correlated with haematocrit, cholinesterase and C-reactive protein (F = 18.63, P < 0.0001). Thus, circulating EPO increases in patients with liver disease, particularly in its more advanced forms. Besides anaemia, both impairment of liver function (possibly via decreased EPO metabolism) and inflammation seem to play contributory roles in elevating serum EPO.
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PMID 
M Pirisi, C Fabris, M P Panozzo, G Soardo, P Toniutto, E Bartoli (1993)  Increased serum phospholipase A2 activity in advanced chronic liver disease as an expression of the acute phase response.   Dis Markers 11: 2-3. 103-111 Sep  
Abstract: Phospholipase A2 (PLA2) modifications were investigated in patients with acute and chronic liver diseases, PLA2 variations were related to indices of liver function as well as to parameters of the acute phase response. Serum PLA2 activity modifications were fluorimetrically measured in 105 patients affected by acute and chronic liver diseases or extra-hepatic diseases. One-way ANOVA demonstrated a significant difference among groups (F = 4.53, P < 0.001); Bonferroni's test for pairwise comparisons showed that patients with hepatocellular carcinoma had higher mean values than subjects with benign extra-hepatic diseases (P < 0.01) and mild chronic liver disease (P < 0.05). Multiple regression analysis, performed choosing PLA2 as the dependent variable and blood urea nitrogen, C-reactive protein, alkaline phosphatase and alpha 1-fetoprotein as predictor variables was significant (multiple R = 0.7056, multiple R2 = 0.4978, F = 15.36, P = < 0.0001). The standardized regression coefficients found to be significant were those of C-reactive protein, blood urea nitrogen and alpha 1-fetoprotein. In conclusion, in patients with chronic liver disease, serum PLA2 activity increases parallel to disease severity and accompanies the expression of proteins of the acute phase response that, like PLA2 activity, increase in serum while liver synthesis declines.
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