- Email: [email protected]
F-10 Emodin partially reverts diet-induced steatosis and completely reverts inflammation and redox status imbalance in rats
S34
Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48
Table 1 Parameter
Common criterion
AKIN
Sensitivity (CI 95%) Specificity (CI 95%) PPV (CI 95%) NPV (CI 95%) PLR (CI 95%) NLR (CI 95%)
0.52 (0.34–0.69) 0.95 (0.91–0.98) 0.61 (0.49–0.73) 0.92 (0.88–0.97) 9.37 (4.83–18.18) 0.51 (0.36–0.73)
0.67 (0.50–0.82) 0.81 (0.76–0.86) 0.37 (0.25–0.50) 0.94 (0.89–0.97) 3.51 (2.41–5.10) 0.41 (0.25–0.67)
Legend: CI = Confidential interval; PPV = positive predictive value; NPV = negative predictive value; PLR = positive likelihood ratio; NLR = negative likelihood ratio.
In univariate and multivariate analysis, common criterion as well as AKIN criteria were shown to be strong independent predictors of in-hospital mortality as well as MELD. When compared with AKIN criteria, common criterion was found to be more accurate in the prediction of in-hospital mortality with a Net Reclassification Improvement of 9.4% (p<0.0001). Conclusions: In our series of patients the common criterion currently used among hepatologists to define AKI seems to be more accurate than AKIN criteria in the prediction of in-hospital mortality.
F-8 Importance of HLA-B in the sustained virological response in patients with chronic hepatitis C treated with peg-IFN and ribavirin K.J. Ibrahim 1 , E. Sigaudo 1 , A. D’Avolio 2 , M. Fadda 3 , P. Caviglia 1 , A. Smedile 1 , G. Di Perri 2 , M. Rizzetto 1 , A. Ciancio 1 1 AOU San Giovani Battista di Torino – SCDU GastroEpatologia, Università di Torino; 2 Ospedale Amedeo di Savoia- Clinica Malattie Infettive; 3 AOU San Giovani Battista di Torino – SC Dietetica e Nutizione Clinica
Background: The importance of HLA-system in the HCV treatment response, has recently been emphasized. Several studies have shown a significative correlation between therapy success and alleles HLA-B*12, B*44, DRB1*04 and DRB1*07. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. Our study aimed to evaluate HLA-B and HLA-DRB1 role and clinical importance in the response to therapeutic treatment with PegIFNα2a/2b and Ribavirin in patients with chronic hepatitis C. Patients and Methods: One hundred and eighty-one patients (M/F 109/72 [genotype 1a = 4%, 1b = 55%, 2a/2c = 18%, 3a = 18% and 4 = 4%] with chronic HCV hepatitis, underwent antiviral treatment [PegIFNα2a 180 μg/week (70%) or PegIFNα2b 15 μg/kg/week (30%)+ ribavirin 1000-1200 mg/die)] and included in the study. At baseline, all patients were evaluated for HLA-B and DRB1 allelles as well as for IL28 polimorphisms. Results: Among studied population, 52% (n=94) achieved a sustained virological response (SVR), 32% (n=58) were non-responder, while 16% (n=29) relapsers. The occurrence of SVR, indipendently of viral genotype, was strongly correlated with presence of HLA-B38 (p=0.03) and weakly with B*08 (p=0.06), while failure to treatment was weakly associated with HLA DRB1* (p=006) and DRB1*07 (p=007). Moreover our analysis confirm that HCV genotype non-1, HCV RNA clearance at week 12 and IL28 polymorphism (rs12979860) CC were positive predictors of SVR. Conclusions: Our study confirms that host genetic factors may be associated with a response to antiviral therapy. The significative association between HLA-B*38 and SVR as well IL28 polimorphisms demonstrate that both genetic factors may be useful in the treatment evaluation and chronic HCV hepatitis management
F-9 The I148M PNPLA3 polymorphism is associated with the clinical presentation and prognosis of hepatocellular carcinoma L. Valenti, B.M. Motta, G. Soardo, C. Bertelli, A. Sangiovanni, R. Rametta, P. Dongiovanni, A. Carnelutti, M. Iavarone, M. Colombo, S. Fargion, A.L. Fracanzani Università degli Studi, Fondazione IRCCS Ca’ Granda Maggiore Policlinico, Milano, Università di Udine. Background & Aims: The Patatin-like phospholipase domain-containing 3
(PNPLA3) rs738409 C>G polymorphism, encoding for the I148M protein variant, is a genetic determinant of liver fat content and influences the severity of liver damage in patients with non-alcoholic and alcoholic fatty liver disease (NAFLD and ALD) and with chronic hepatitis C (CHC). Furthermore, the I148M polymorphism has been associated with hepatocellular carcinoma (HCC) in CHC and ALD. Aim of the study was to evaluate the association between PNPLA3 148M, clinical features, and the outcome in Italian patients with HCC. Methods: We considered 316 consecutive HCC patients (M/F 251/75, age 68±9 yrs) referred to tertiary care centers with available DNA samples. HCC arose during follow up in 247 and was incidental in the remaining 69, in 8 cases HCC occurred in non-cirrhotic liver, and was diagnosed according to EASL criteria. Results: In HCC patients, the frequency distribution of the rs738409 SNP was 139 p.148I/I (44%), 132 p.148I/M (42%), and 49 (15%) p.148G/G (p<10ˆ-12 vs. healthy controls). The p.148G variant predisposing to steatosis was over-represented in patients with metabolic/toxic liver disease (NAFLD/ALD/hemochromatosis/cryptogenic, n=69) than in those with chronic viral hepatitis (HBV/HCV, n=247): 26% I/I, 48% I/M, 26% M/M vs. 48% I/I, 40% I/M, 12% M/M, respectively (p=0.001). Length of follow-up before HCC development, age at diagnosis, sex distribution, and diabetes prevalence were not significantly different among PNPLA3 genotypes. However, the size of monofocal HCC lesion (n=89, 2.4±1.1 cm I/I; n=61 2.6±1.2 I/M; n=31, 3.0±1.6 M/M; p=0.05 for trend), as well as the prevalence of BCLC stage B-D (13% I/I, 28% I/M, 33% M/M; p=0.0009 for trend) increased progressively with the number of 148M alleles. Homozygosity for the 148M allele was associated with increased mortality (median 36, IQR 24-132 vs. 72, 36-120 months, p=0.003 at Wilcoxon; HR 1.94, 95% CI 1.1-3.3 after correction for age, sex, etiology of liver disease, smoking status, and BCLC stage A vs. B-D at Cox regression). Conclusions: The 148M PNPLA3 allele is over-represented in HCC, in particular in those arising in metabolic/toxic liver diseases, and might be associated with larger monofocal lesions, more advanced HCC stage at presentation, and a worse prognosis.
F-10 Emodin partially reverts diet-induced steatosis, and completely reverts inflammation and redox status imbalance in rats N. Panera 1 , A. Pastore 1 , S. Ceccarelli 1 , S. Petrini 1 , G. Bruscalupi 2 , M. Massimi 3 , F. Piemonte 1 , A. Alisi 1 , V. Nobili 1 1
“Bambino Gesù” Children’s Hospital and Research Institute, Rome, Italy; of Biology and Biotechnology “C. Darwin”, “La Sapienza” University, Rome, Italy; 3 Department of Basic and Applied Biology, University of L’Aquila, L’Aquila, Italy 2 Department
Background/aim: High-fat and/or high-carbohydrate diets may promote liver steatosis alone or associated with necro-inflammation and fibrosis (steatohepatitis). Lifestyle changes, including correction of dietetic regimen coupled with exercise, is the mainstay of therapeutic intervention in diet-induced steatosis. However, recently, several studies have emphasized the hepatoprotective effect of some natural agents. Here, we investigated the potential therapeutic effects of Emodin, an anthraquinone derivative with anti-oxidant and anti-cancer properties, in rats that develop diet-induced hepatosteatosis and steatohepatitis. Methods: Sprague-Dawley rats were fed, for 5 weeks, with standard diet (SD), high-fat diet (Hfa), high-fat/high-fructose diet (HFa/HFr). After 10 weeks, Emodin was added to the drinking water of a part of SD and HFa/HFr rats. The experiment was termed after additional 10 weeks. Results: Emodin daily treatment caused a weight gain (20-30%) in all rats, even though it partially reverted (a 50% of reduction) liver accumulation of triglycerides both in HFa and HFa/HFr rats. Furthermore, Emodin exerted antiinflammatory activity by inhibiting the HFa- and HFa/HFr-induced increase of circulating levels of some cytokines, including tumor necrosis factor-alpha, interleukins 6 and 1-beta. Finally, the treatment with Emodin significantly reduced the levels of proteins bound to glutathione (glutathionylation) in HFaand HFa/HFr animals restoring levels of gluthathionylation similar to SD rats. In particular, we observed that Emodin was also able to revert the effects of
Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48 the HFa and HFa/HFr on the glutathionylation, phosphorylation and activity of phosphatase and tensin homolog (PTEN). Conclusions: In conclusion, we demonstrated that natural agents, such as Emodin may counteract the development of diet-induced steatohepatitis, preserving the liver from pro-inflammatory and pro-oxidant damage and reducing steatosis. These findings are promising, regarding the possibility to use Emodin as treatment.
F-11 Combination of radiofrequency ablation and transcatheter arterial chemoembolization improves survival in advanced hepatocellular carcinoma complicating liver cirrhosis P. Ventura 1 , M. De Santis 2 , F. Bonetti 1 , G. Venturelli 1 , P. Di Gangi 1 , M. Marcacci 1 , P. Torricelli 2 , A. Pietrangelo 1 1 Medicine II, Dept. of Medicines, Emergency Medicine and Medical Specialties; 2 Radiology I, Dept. of Diagnostics and Imagine Services; University of Modena and Reggio Emilia, Modena, Italy
Background: Treatment of hepatocellular carcinoma (HCC) still remains a controversial issue. In particular, for patients with HCC status exceeding the criteria for “curative” options (advanced HCC) there is no defined standard of therapy. Aim: To evaluate efficacy of combined treatment with radiofrequency ablation (RFA) and transcatether arterial chemio-embolization (TACE) in advanced HCC. Materials and Methods: We performed a retrospective study to compare the cumulative survival rate of patients with advanced HCC treated with combined therapy (simultaneous application of TACE and RFA) [RFA-TACE group, n=35] vs. those treated only by TACE [TACE group, n=36] or those treated only by conservative option [Control group, n=36]. HCC was confirmed by imaging and/or histology. All patients were monitored at one-three months after treatment and every six months by imaging to check for treatment success and/or HCC recurrence. In order to minimize possible bias due to the retrospective design, a propensity score approach was used in analysing the results. Results: The median survival time were 31 months for TACE-RFA group, 21 months for patients in TACE group and 10 months in control group, respectively. The 6-month survival rate was 96%, 90% and 78% in TACE-RFA group, TACE group and control group, respectively; the 1-year survival rate was 89%, 75% and 20.3%. At 3 years from HCC diagnosis, 6% of control group patients were alive, versus 34% and 45% of TACE and TACE-RFA group, respectively. Survival rates difference between groups were significant (p=0.011 and p<0.001 TACE and Controls with respect to TACE-RFA group). Treatment allocation (HR 2.14, p=0.022), and complete treatment response were important independent predictors (HR 3.25, p=0.018) of survival. Conclusion: Based on the results of this study we conclude that the combination of RFA and TACE may represent a promising approach for the treatment of advanced HCC complicating liver cirrhosis. nevertheless, a better definition of patient’s characteristics and technical approaches together with larger scale-randomized trials are needed.
F-12 Epigenetic modulation of CD40 ligand leads to hyper IgM in patients with primary biliary cirrhosis A. Lleo 1 , J. Liao 2,3 , F. Bernuzzi 1 , G. Lanzi 4 , Q. Lu 3,4 , M.E. Gershwin 5 , P. Invernizzi 1,5 1 Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 2 Department of Dermatology, Second Xiangya Hospital, Central South University; 3 Hunan Key Laboratory of Medical Epigenomics, Hunan, PR China; 4 “A. Nocivelli” Institute for Molecular Medicine and Pediatric Clinic, University of Brescia, Brescia, Italy; 5 Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
Patients with Primary Biliary Cirrhosis (PBC) characteristically show circu-
S35
lating anti-mitochondrial antibodies (AMAs), liver infiltrating autoreactive T lymphocytes against mitochondrial antigens, and high levels of IgM. Naive T cells require contact with appropriately activated antigen presenting cells (APC) in order to be primed. The CD40-CD40L system constitutes one of the fundamental accessory systems in T cell priming, as well as B-cell terminal maturation, and immunoglobulin (Ig) class-switch recombination. Genetic defects in the CD40L lead to a disorder characterized by elevated concentrations of sera IgM and immunodeficiency. We therefore hypothesized that CD40L may play a key role in the pathogenesis of the elevated sera IgM. Methods: Genomic DNA was isolated from circulating CD4+ and CD8+ T cells isolated from PBC patients (n=20), and unaffected controls (n=20). All patients with PBC were women and had readily detectable AMA; the diagnosis was made based on internationally accepted criteria. The mean age was 64 years old (range 44-87 years) and 70% of them were taking ursodiol. DNA methylation of the CD40L promoter was analyzed by bisulfite sequencing. In order to determine the potential contribution of the presence of mutations of the CD40L gene that could influence IgM levels, we sequenced all 5 exons of the CD40L gene in genomic DNA samples isolated from CD4+ T cells from PBC patients and controls. Results: We herein demonstrate significantly lower levels of DNA methylation of the CD40L promoter in CD4+ T cells from PBC patients as compared with controls, and this decreased methylation was inversely correlated with levels of serum IgM in PBC patients. No detectable difference in the level of CD40L promoter methylation in isolated CD8+ T cells was observed between PBC patients and controls. Conclusion: The findings of an absence of genetic modifications of the CD40L gene in concert with decreased DNA methylation of the CD40L promoter in PBC patients suggests that environmental factors play a major role in the pathogenesis of elevated sera IgM in PBC.
F-13 Efficacy and safety of combination therapy with pegylated interferon and ribavirin in aged patients with chronic hepatitis C G. Abbati, P. Ventura, C. Sardini, A. Vegetti, F. Pileri, S. Cagnacci, G. Venturelli, F. Incerti, A. Pietrangelo Medicine II, Dept. Medicines, Emergency Medicine and Medical Specialties, University of Modena and Reggio Emilia Background & Aims: Combination therapy with pegylated interferon (PEGIFN) and ribavirin has significantly improved virus eradication rate in patients affected by HCV-related chronic hepatitis (C-HC). However, only few data are available with respect to efficacy and safety of this therapy in aged patients. This study aimed at investigating efficacy and tolerability of combination therapy in aged patients with CH-C. Methods: 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C (genotype 1, n=266; genotype 2, n=112, genotype 3, n=72, genotype 4, n=23), of whom 68 (14.4%) over 65 years old (mean age 69±2 years), were treated with Peg-IFN (alpha-2a or alpha-2b) plus ribavirin according to international guidelines from January 2007 to July 2011. These patients were assessed for sustained viral response (SVR) rate and for all known main predictors of SVR in CH-C. Results: The overall SVR rate resulted similar in both age groups [270/405 (66.6%) in subjects <65 years vs. 41/68 (60.3%) in subjects ≥65 years, respectively, p=0.334)]. Overall, therapy discontinuance rate was low, with no significant difference between patients over or under age 65 (4.4% vs. 4.9%, respectively), the most common reason for discontinuance being anemia in both groups.For patients over 65, at multivariate analysis, non-naïve status, EVR and use of hematological growth factors were independent predictors of SVR. Factors independently related to EVR at multivariate analysis were non-naive, staging, genotype 2-3 vs. genotype1-4 and use of hematological growth factors Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin therapy. The appropriate use of hematological factors in these patients may be useful to achieve a significant reduction in the rate of therapy discontinuation due to hematological side-effects. The response-guided therapy may be applied in predicting therapy efficacy in this patient group.
Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48
Table 1 Parameter
Common criterion
AKIN
Sensitivity (CI 95%) Specificity (CI 95%) PPV (CI 95%) NPV (CI 95%) PLR (CI 95%) NLR (CI 95%)
0.52 (0.34–0.69) 0.95 (0.91–0.98) 0.61 (0.49–0.73) 0.92 (0.88–0.97) 9.37 (4.83–18.18) 0.51 (0.36–0.73)
0.67 (0.50–0.82) 0.81 (0.76–0.86) 0.37 (0.25–0.50) 0.94 (0.89–0.97) 3.51 (2.41–5.10) 0.41 (0.25–0.67)
Legend: CI = Confidential interval; PPV = positive predictive value; NPV = negative predictive value; PLR = positive likelihood ratio; NLR = negative likelihood ratio.
In univariate and multivariate analysis, common criterion as well as AKIN criteria were shown to be strong independent predictors of in-hospital mortality as well as MELD. When compared with AKIN criteria, common criterion was found to be more accurate in the prediction of in-hospital mortality with a Net Reclassification Improvement of 9.4% (p<0.0001). Conclusions: In our series of patients the common criterion currently used among hepatologists to define AKI seems to be more accurate than AKIN criteria in the prediction of in-hospital mortality.
F-8 Importance of HLA-B in the sustained virological response in patients with chronic hepatitis C treated with peg-IFN and ribavirin K.J. Ibrahim 1 , E. Sigaudo 1 , A. D’Avolio 2 , M. Fadda 3 , P. Caviglia 1 , A. Smedile 1 , G. Di Perri 2 , M. Rizzetto 1 , A. Ciancio 1 1 AOU San Giovani Battista di Torino – SCDU GastroEpatologia, Università di Torino; 2 Ospedale Amedeo di Savoia- Clinica Malattie Infettive; 3 AOU San Giovani Battista di Torino – SC Dietetica e Nutizione Clinica
Background: The importance of HLA-system in the HCV treatment response, has recently been emphasized. Several studies have shown a significative correlation between therapy success and alleles HLA-B*12, B*44, DRB1*04 and DRB1*07. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. Our study aimed to evaluate HLA-B and HLA-DRB1 role and clinical importance in the response to therapeutic treatment with PegIFNα2a/2b and Ribavirin in patients with chronic hepatitis C. Patients and Methods: One hundred and eighty-one patients (M/F 109/72 [genotype 1a = 4%, 1b = 55%, 2a/2c = 18%, 3a = 18% and 4 = 4%] with chronic HCV hepatitis, underwent antiviral treatment [PegIFNα2a 180 μg/week (70%) or PegIFNα2b 15 μg/kg/week (30%)+ ribavirin 1000-1200 mg/die)] and included in the study. At baseline, all patients were evaluated for HLA-B and DRB1 allelles as well as for IL28 polimorphisms. Results: Among studied population, 52% (n=94) achieved a sustained virological response (SVR), 32% (n=58) were non-responder, while 16% (n=29) relapsers. The occurrence of SVR, indipendently of viral genotype, was strongly correlated with presence of HLA-B38 (p=0.03) and weakly with B*08 (p=0.06), while failure to treatment was weakly associated with HLA DRB1* (p=006) and DRB1*07 (p=007). Moreover our analysis confirm that HCV genotype non-1, HCV RNA clearance at week 12 and IL28 polymorphism (rs12979860) CC were positive predictors of SVR. Conclusions: Our study confirms that host genetic factors may be associated with a response to antiviral therapy. The significative association between HLA-B*38 and SVR as well IL28 polimorphisms demonstrate that both genetic factors may be useful in the treatment evaluation and chronic HCV hepatitis management
F-9 The I148M PNPLA3 polymorphism is associated with the clinical presentation and prognosis of hepatocellular carcinoma L. Valenti, B.M. Motta, G. Soardo, C. Bertelli, A. Sangiovanni, R. Rametta, P. Dongiovanni, A. Carnelutti, M. Iavarone, M. Colombo, S. Fargion, A.L. Fracanzani Università degli Studi, Fondazione IRCCS Ca’ Granda Maggiore Policlinico, Milano, Università di Udine. Background & Aims: The Patatin-like phospholipase domain-containing 3
(PNPLA3) rs738409 C>G polymorphism, encoding for the I148M protein variant, is a genetic determinant of liver fat content and influences the severity of liver damage in patients with non-alcoholic and alcoholic fatty liver disease (NAFLD and ALD) and with chronic hepatitis C (CHC). Furthermore, the I148M polymorphism has been associated with hepatocellular carcinoma (HCC) in CHC and ALD. Aim of the study was to evaluate the association between PNPLA3 148M, clinical features, and the outcome in Italian patients with HCC. Methods: We considered 316 consecutive HCC patients (M/F 251/75, age 68±9 yrs) referred to tertiary care centers with available DNA samples. HCC arose during follow up in 247 and was incidental in the remaining 69, in 8 cases HCC occurred in non-cirrhotic liver, and was diagnosed according to EASL criteria. Results: In HCC patients, the frequency distribution of the rs738409 SNP was 139 p.148I/I (44%), 132 p.148I/M (42%), and 49 (15%) p.148G/G (p<10ˆ-12 vs. healthy controls). The p.148G variant predisposing to steatosis was over-represented in patients with metabolic/toxic liver disease (NAFLD/ALD/hemochromatosis/cryptogenic, n=69) than in those with chronic viral hepatitis (HBV/HCV, n=247): 26% I/I, 48% I/M, 26% M/M vs. 48% I/I, 40% I/M, 12% M/M, respectively (p=0.001). Length of follow-up before HCC development, age at diagnosis, sex distribution, and diabetes prevalence were not significantly different among PNPLA3 genotypes. However, the size of monofocal HCC lesion (n=89, 2.4±1.1 cm I/I; n=61 2.6±1.2 I/M; n=31, 3.0±1.6 M/M; p=0.05 for trend), as well as the prevalence of BCLC stage B-D (13% I/I, 28% I/M, 33% M/M; p=0.0009 for trend) increased progressively with the number of 148M alleles. Homozygosity for the 148M allele was associated with increased mortality (median 36, IQR 24-132 vs. 72, 36-120 months, p=0.003 at Wilcoxon; HR 1.94, 95% CI 1.1-3.3 after correction for age, sex, etiology of liver disease, smoking status, and BCLC stage A vs. B-D at Cox regression). Conclusions: The 148M PNPLA3 allele is over-represented in HCC, in particular in those arising in metabolic/toxic liver diseases, and might be associated with larger monofocal lesions, more advanced HCC stage at presentation, and a worse prognosis.
F-10 Emodin partially reverts diet-induced steatosis, and completely reverts inflammation and redox status imbalance in rats N. Panera 1 , A. Pastore 1 , S. Ceccarelli 1 , S. Petrini 1 , G. Bruscalupi 2 , M. Massimi 3 , F. Piemonte 1 , A. Alisi 1 , V. Nobili 1 1
“Bambino Gesù” Children’s Hospital and Research Institute, Rome, Italy; of Biology and Biotechnology “C. Darwin”, “La Sapienza” University, Rome, Italy; 3 Department of Basic and Applied Biology, University of L’Aquila, L’Aquila, Italy 2 Department
Background/aim: High-fat and/or high-carbohydrate diets may promote liver steatosis alone or associated with necro-inflammation and fibrosis (steatohepatitis). Lifestyle changes, including correction of dietetic regimen coupled with exercise, is the mainstay of therapeutic intervention in diet-induced steatosis. However, recently, several studies have emphasized the hepatoprotective effect of some natural agents. Here, we investigated the potential therapeutic effects of Emodin, an anthraquinone derivative with anti-oxidant and anti-cancer properties, in rats that develop diet-induced hepatosteatosis and steatohepatitis. Methods: Sprague-Dawley rats were fed, for 5 weeks, with standard diet (SD), high-fat diet (Hfa), high-fat/high-fructose diet (HFa/HFr). After 10 weeks, Emodin was added to the drinking water of a part of SD and HFa/HFr rats. The experiment was termed after additional 10 weeks. Results: Emodin daily treatment caused a weight gain (20-30%) in all rats, even though it partially reverted (a 50% of reduction) liver accumulation of triglycerides both in HFa and HFa/HFr rats. Furthermore, Emodin exerted antiinflammatory activity by inhibiting the HFa- and HFa/HFr-induced increase of circulating levels of some cytokines, including tumor necrosis factor-alpha, interleukins 6 and 1-beta. Finally, the treatment with Emodin significantly reduced the levels of proteins bound to glutathione (glutathionylation) in HFaand HFa/HFr animals restoring levels of gluthathionylation similar to SD rats. In particular, we observed that Emodin was also able to revert the effects of
Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48 the HFa and HFa/HFr on the glutathionylation, phosphorylation and activity of phosphatase and tensin homolog (PTEN). Conclusions: In conclusion, we demonstrated that natural agents, such as Emodin may counteract the development of diet-induced steatohepatitis, preserving the liver from pro-inflammatory and pro-oxidant damage and reducing steatosis. These findings are promising, regarding the possibility to use Emodin as treatment.
F-11 Combination of radiofrequency ablation and transcatheter arterial chemoembolization improves survival in advanced hepatocellular carcinoma complicating liver cirrhosis P. Ventura 1 , M. De Santis 2 , F. Bonetti 1 , G. Venturelli 1 , P. Di Gangi 1 , M. Marcacci 1 , P. Torricelli 2 , A. Pietrangelo 1 1 Medicine II, Dept. of Medicines, Emergency Medicine and Medical Specialties; 2 Radiology I, Dept. of Diagnostics and Imagine Services; University of Modena and Reggio Emilia, Modena, Italy
Background: Treatment of hepatocellular carcinoma (HCC) still remains a controversial issue. In particular, for patients with HCC status exceeding the criteria for “curative” options (advanced HCC) there is no defined standard of therapy. Aim: To evaluate efficacy of combined treatment with radiofrequency ablation (RFA) and transcatether arterial chemio-embolization (TACE) in advanced HCC. Materials and Methods: We performed a retrospective study to compare the cumulative survival rate of patients with advanced HCC treated with combined therapy (simultaneous application of TACE and RFA) [RFA-TACE group, n=35] vs. those treated only by TACE [TACE group, n=36] or those treated only by conservative option [Control group, n=36]. HCC was confirmed by imaging and/or histology. All patients were monitored at one-three months after treatment and every six months by imaging to check for treatment success and/or HCC recurrence. In order to minimize possible bias due to the retrospective design, a propensity score approach was used in analysing the results. Results: The median survival time were 31 months for TACE-RFA group, 21 months for patients in TACE group and 10 months in control group, respectively. The 6-month survival rate was 96%, 90% and 78% in TACE-RFA group, TACE group and control group, respectively; the 1-year survival rate was 89%, 75% and 20.3%. At 3 years from HCC diagnosis, 6% of control group patients were alive, versus 34% and 45% of TACE and TACE-RFA group, respectively. Survival rates difference between groups were significant (p=0.011 and p<0.001 TACE and Controls with respect to TACE-RFA group). Treatment allocation (HR 2.14, p=0.022), and complete treatment response were important independent predictors (HR 3.25, p=0.018) of survival. Conclusion: Based on the results of this study we conclude that the combination of RFA and TACE may represent a promising approach for the treatment of advanced HCC complicating liver cirrhosis. nevertheless, a better definition of patient’s characteristics and technical approaches together with larger scale-randomized trials are needed.
F-12 Epigenetic modulation of CD40 ligand leads to hyper IgM in patients with primary biliary cirrhosis A. Lleo 1 , J. Liao 2,3 , F. Bernuzzi 1 , G. Lanzi 4 , Q. Lu 3,4 , M.E. Gershwin 5 , P. Invernizzi 1,5 1 Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 2 Department of Dermatology, Second Xiangya Hospital, Central South University; 3 Hunan Key Laboratory of Medical Epigenomics, Hunan, PR China; 4 “A. Nocivelli” Institute for Molecular Medicine and Pediatric Clinic, University of Brescia, Brescia, Italy; 5 Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
Patients with Primary Biliary Cirrhosis (PBC) characteristically show circu-
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lating anti-mitochondrial antibodies (AMAs), liver infiltrating autoreactive T lymphocytes against mitochondrial antigens, and high levels of IgM. Naive T cells require contact with appropriately activated antigen presenting cells (APC) in order to be primed. The CD40-CD40L system constitutes one of the fundamental accessory systems in T cell priming, as well as B-cell terminal maturation, and immunoglobulin (Ig) class-switch recombination. Genetic defects in the CD40L lead to a disorder characterized by elevated concentrations of sera IgM and immunodeficiency. We therefore hypothesized that CD40L may play a key role in the pathogenesis of the elevated sera IgM. Methods: Genomic DNA was isolated from circulating CD4+ and CD8+ T cells isolated from PBC patients (n=20), and unaffected controls (n=20). All patients with PBC were women and had readily detectable AMA; the diagnosis was made based on internationally accepted criteria. The mean age was 64 years old (range 44-87 years) and 70% of them were taking ursodiol. DNA methylation of the CD40L promoter was analyzed by bisulfite sequencing. In order to determine the potential contribution of the presence of mutations of the CD40L gene that could influence IgM levels, we sequenced all 5 exons of the CD40L gene in genomic DNA samples isolated from CD4+ T cells from PBC patients and controls. Results: We herein demonstrate significantly lower levels of DNA methylation of the CD40L promoter in CD4+ T cells from PBC patients as compared with controls, and this decreased methylation was inversely correlated with levels of serum IgM in PBC patients. No detectable difference in the level of CD40L promoter methylation in isolated CD8+ T cells was observed between PBC patients and controls. Conclusion: The findings of an absence of genetic modifications of the CD40L gene in concert with decreased DNA methylation of the CD40L promoter in PBC patients suggests that environmental factors play a major role in the pathogenesis of elevated sera IgM in PBC.
F-13 Efficacy and safety of combination therapy with pegylated interferon and ribavirin in aged patients with chronic hepatitis C G. Abbati, P. Ventura, C. Sardini, A. Vegetti, F. Pileri, S. Cagnacci, G. Venturelli, F. Incerti, A. Pietrangelo Medicine II, Dept. Medicines, Emergency Medicine and Medical Specialties, University of Modena and Reggio Emilia Background & Aims: Combination therapy with pegylated interferon (PEGIFN) and ribavirin has significantly improved virus eradication rate in patients affected by HCV-related chronic hepatitis (C-HC). However, only few data are available with respect to efficacy and safety of this therapy in aged patients. This study aimed at investigating efficacy and tolerability of combination therapy in aged patients with CH-C. Methods: 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C (genotype 1, n=266; genotype 2, n=112, genotype 3, n=72, genotype 4, n=23), of whom 68 (14.4%) over 65 years old (mean age 69±2 years), were treated with Peg-IFN (alpha-2a or alpha-2b) plus ribavirin according to international guidelines from January 2007 to July 2011. These patients were assessed for sustained viral response (SVR) rate and for all known main predictors of SVR in CH-C. Results: The overall SVR rate resulted similar in both age groups [270/405 (66.6%) in subjects <65 years vs. 41/68 (60.3%) in subjects ≥65 years, respectively, p=0.334)]. Overall, therapy discontinuance rate was low, with no significant difference between patients over or under age 65 (4.4% vs. 4.9%, respectively), the most common reason for discontinuance being anemia in both groups.For patients over 65, at multivariate analysis, non-naïve status, EVR and use of hematological growth factors were independent predictors of SVR. Factors independently related to EVR at multivariate analysis were non-naive, staging, genotype 2-3 vs. genotype1-4 and use of hematological growth factors Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin therapy. The appropriate use of hematological factors in these patients may be useful to achieve a significant reduction in the rate of therapy discontinuation due to hematological side-effects. The response-guided therapy may be applied in predicting therapy efficacy in this patient group.