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Impact of rifaximin in the prevention of bacterial infections in cirrhosis
Abstracts / Digestive and Liver Disease 47S (2015) e43–e66
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F-22
FIRST STEPS TOWARDS UNDERSTANDING THE DYNAMIC EVOLUTION OF GUT MICROBIOTA IN DIFFERENT STAGES OF LIVER DISEASE
PREVALENCE OF HEPATITIS E IN TERTIARY HOSPITAL CENTRE IN NORTHERN ITALY
F.R. Ponziani 1 , S. Pecere 1 , F. Paroni Sterbini 2 , V. Petito 1 , M. Siciliano 1 , T. Di Rienzo 1 , A. Palladini 2 , D. Zambrano 1 , F. Franceschi 1 , E. Gaetani 1 , F. Scaldaferri 1 , L. Masucci 2 , M. Sanguinetti 2 , A. Gasbarrini 1 1 Internal Medicine Department, Gastroenterology Division, Catholic University Of Sacred Heart of Rome, Rome, Italy 2 Microbiology Department, Catholic University Of Sacred Heart of Rome, Rome, Italy
INTRODUCTION: Liver cirrhosis is associated to intestinal barrier derangement and dysbiosis. AIM: To preliminary describe gut microbiota modifications in a population of Italian patients with liver cirrhosis. PATIENTS AND METHODS: Fecal samples were collected in 13 cirrhotic patients and 10 healthy controls, no exposed for at least one month to antibiotics, prebiotics, probiotics and bowel colonoscopy preparation. Gut microbiota composition was assessed by a metagenomic gene-targeted approach (16S rRNA), following DNA isolation from stool samples stored at–80 ◦ C. Data were analyzed in Qiime. Non parametric tests were used for the final statistical analysis. RESULTS: The enterotypification of the 23 subjects was comparable to that of the Western general population, with a prevalence of Bacteroides (enterotype 1, 77%, often overlapping with enterotype 3, 18%) with no inter- or intra-group differences between cirrhotics and healthy controls. A trend toward an unbalance between the Firmicutes to Bacteroidetes ratio was found throughout the different Child Pugh stages (close to 1 in Child A, reduced to half in Child B and to ¼ in Child C p = 0.081). Compared to healthy individuals, cirrhotics microbiota was more enriched in Bacilli (Lactobacillaceae, Streptococcaceae, Enterococcaceae; p = 0.001), especially in case of intermediate stage liver disease (abundance in Child B patients 48.6%; p = 0.008). Clostridia (Clostridiaceae, Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Clostridiaceae, Peptostreptococcaceae, Peptococcaceae) were the most abundant in the initial phases of the disease (62.3% in Child A patients p = 0.06). Patients with at least one clinical sign of decompensation lost the relative abundance of Clostridia (abundance 62.3% in compensated patients vs 20.8% in decompensated ones vs 35.4% in healthy controls p = 0.04). CONCLUSION: Liver cirrhosis is a fascinating model of gut microbiota modifications, that are connected with the progression of liver impairment. http://dx.doi.org/10.1016/j.dld.2015.01.115
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V. Zuccaro 1 , P. Columpsi 1 , S. Paolucci 2 , M. Mariani 1 , S. Toppino 1 , A. Malfitano 1 , A. Parisi 1 , S.F.A. Patruno 1 , F. Baldanti 2 , R. Bruno 1 1 Department of Infectious Diseases–IRCCS San Matteo - University of Pavia, Pavia, Italy 2 Virology Unit IRCCS San Matteo - University of Pavia, Pavia, Italy
Introduction: In developed countries, hepatitis E is a zoonosis usually caused by the genotypes 3 and 4. In Italy the prevalence of anti-HEV is 1-5% among the healthy population. A large prospective study has shown that HEV accounts for approximately 10% of acute non A, non B hepatitis cases in Italy. Aim: The aim of the study was to evaluate the prevalence of hepatitis E among patients admitted to the Division of Infectious and tropical Disease for acute hepatitis without evidence of autoimmunity and antibody against HAV-HBV-HCV. Materials and Methods Results: A total of 970 patients were admitted to Division of Tropical and Infectious Diseases from 2013 to 2014. Among them 27 had acute hepatitis and 3 (11%) were positive for hepatitis E. All were anti-HEV IgM and IgG positive and were also positive for HEV-RNA, viral genotype was 3 subtype F in all cases. All HEV patients were living from Pavia and denied having travelled abroad. Diagnosis of hepatitis E was based on the presence of IgM anti-HEV and confirmed by the detection of HEVRNA - RTPCR on patients samples. Viral isolates were sequenced to characterize subtypes. Two cases with acute disease had a selflimited course with AST-ALT normalization within 3-6 weeks. One patient died from acute on chronic liver disease. All cases showed high level of amylases during the acute phase. Conclusions: This is the first report of hepatitis E in the Pavia area and it confirms the increasing trend of prevalence of autochthonous hepatitis E in our country. The increased prevalence might be related either to the spread of the HEV virus in our country and to the implementation of HEV screening in patients with acute hepatitis. In the case of acute hepatitis with high amylases level should prompt exclude HEV infection. http://dx.doi.org/10.1016/j.dld.2015.01.116 F-23 IMPACT OF RIFAXIMIN IN THE PREVENTION OF BACTERIAL INFECTIONS IN CIRRHOSIS M. Mariani 1 , L. Scudeller 2 , S.F.A. Patruno 1 , V. Zuccaro 1 , P. Columpsi 1 , S. Toppino 1 , A. Malfitano 1 , A. Parisi 1 , G. Filice 1 , R. Bruno 1 1
Division of Infectious and Tropical Diseases–IRCCS San Matteo - University of Pavia, Pavia, Italy 2 Scientific Direction, IRCCS Policlinico San Matteo, Pavia, Italy Background and aims: Infectious events represent a leading factor able to accelerate the progression from compensated to decompensated stage of cirrhosis, with a subsequent worsening of the prognosis. Due to the high frequency of infectious complications in cirrhotic patients, a great effort was made in order to improve the survival rate. Rifaximin was advanced as a possible primary prophylactic therapy against spontaneous bacterial infections. We retrospectively investigated the role of this antibiotic in
e54
Abstracts / Digestive and Liver Disease 47S (2015) e43–e66
reducing the proportion of infected patients in treated and nontreated groups. Methods: We enrolled 649 patients whose clinical and personal data, prescribed therapy, microbiological findings and laboratory tests were collected from previous discharge letters and our institution database. We excluded patients with ACLF and acute hepatitis. Aetiology, drug resistance and site of infection were collected as well. Results: Risk of developing bacterial infections was significantly lower in patients treated with rifaximin (6 month of treatment, 10 days per month, 400gr t.i.d.) (OR 0.29; 95% CI 0.20-0.40, p < 0.001) compared to those not treated. Moreover, in our cohort we find out a prevalence of infections sustained by Gram-positive bacteria (61.5% of isolations). Conclusions: Rifaximin continuous treatment turned out to be a very effective factor involved in bacterial infections prevention in cirrhotic patients. Our study showed a shift in general bacterial prevalence among pathogens to Gram positive, this finding should be considered as well before administering an empirical therapy in cirrhotic patients. http://dx.doi.org/10.1016/j.dld.2015.01.117 F-24 SERUM ALPHA-FETOPROTEIN MODIFICATION (DELTA-AFP) IS A HIGHLY SPECIFIC TOOL TO SUSPECT HCC RECURRENCE AFTER LIVER TRANSPLANTATION F.R. Ponziani 1,∗ , S. Bhoori 1 , M. Bongini 1 , M. Flores 1 , C. Muscarà 1 , V. Mazzaferro 1 1 Liver Transplant, Hepatobiliary and Gastrointestinal Surgery, Hepatology National Cancer Insitute of Milan, Milan, Italy
Introduction: Alpha-fetoprotein (AFP) is the main tumor marker of hepatocellular carcinoma (HCC). Despite AFP values at listing have been used to predict HCC recurrence after liver transplantation (LT), its role in patients’ surveillance after LT has not been established yet. Aim: To investigate the usefulness of serum AFP modification to suspect recurrence in patients who previously underwent LT for HCC. Materials and Methods Results: We investigated all consecutive patients undergoing LT for HCC within Milan or up-to-seven criteria from January 2004 to December 2013. Serum AFP was collected at the time of LT and every 6-months for 2 years and every year thereafter. Patients surveillance consisted in semiannual abdominal ultrasound or CT scan for the first 5-years, then every year. 231 LT recipients were investigated (median age 61 (14-64), 89% males, 30% HBV, 51.5% HCV, 4% coinfected, 10% alcohol, 8% other, 4% HIV); 31 of them (13%) experienced HCC recurrence. Among HCC recurrence-free patients, 24 (10%) developed cirrhosis or liver failure, severe hepatitis or alcohol abuse during follow-up; since their median AFP values had higher peaks, they were excluded to avoid biases. Univariate analysis failed to demonstrate any association between serum AFP at any timepoint and HCC recurrence, while its modification (difference between the highest AFP value detected during follow-up or the value detected at recurrence, and the lowest serum AFP value, named “delta-AFP”) was strongly associated with HCC recurrence (p < 0.0001). Multivariable analysis confirmed delta-AFP as the only independent predictive factor of HCC recurrence (OR 1.28, 95%CI 1.116, 1.470; p = 0.001). The accuracy of delta-AFP in predicting recurrence was 71.5% (95%CI
65% > 77.5%), with the best identified cut-off value of 6.57 ng/ml (sensitivity 61.3% specificity 100%, NPV 96% PPV 100%). Conclusions: Delta-AFP is a very easy-to-use and highly specific tool to suspect HCC recurrence after LT. http://dx.doi.org/10.1016/j.dld.2015.01.118 F-25 CLINICAL PRESENTATION, TREATMENT AND OUTCOME OF ALCOHOL- AND HEPATITIS C VIRUS- RELATED HEPATOCELLULAR CARCINOMA IN THE NEW CENTURY: COMPARISON BEFORE AND AFTER ADJUSTMENT WITH PROPENSITY SCORE ANALYSIS L. Bucci 1 , F. Garuti 1 , V. Camelli 1 , B. Lenzi 1 , M. Bernardi 1 , F. Trevisani 1 , for the Italian Liver Cancer (ITA.LI.CA) group 1 Dipartimento di Scienze Mediche e Chirurgiche Alma Mate Studiorum - University of Bologna, Bologna, Italy
Introduction and aims: Hepatitis C virus (HCV) and alcohol abuse are the main causes of hepatocellular carcinoma (HCC) in Western world, accounting for about 60% and 20% of cases, respectively. This study aimed at comparing the clinical presentation and outcome of alcohol- and HCV- related HCC diagnosed in the new century. Materials and Methods: 1844 HCV and 636 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC from January 2000 to December 2012 were compared for age, gender, type of diagnosis, Barcelona Clinic Liver Cancer (BCLC), tumor gross pathology, portal vein thrombosis (PVT), esophageal varices, model for end stage liver disease (MELD), Child-Pugh class, alpha-fetoprotein (AFP), treatment and survival. For survival analysis, a propensity matching model was performed to minimize imbalances of prognostic factors between groups. Results: Underlying cirrhosis was present in 96% of both alcoholic and HCV patients. Alcoholic patients were significantly younger and more likely male, diagnosed with a tumor outside surveillance, in intermediate and terminal BCLC stage and in a worse hepatic function setting. Consequently, the overall survival was decreased in alcoholic compared to HCV patients [median (95% C.I.): 34.5 (28.7-40.2) vs 43.6 (40.9-46.3) months; p < 0.001]. A one-to-one matching after propensity score adjustment according to age, gender, type of diagnosis, BCLC stage, tumor gross pathology, PVT and treatment was performed. This analysis selected 354 patients per group, well balanced for baseline prognostic factors. The overall survival did not differ any longer between alcoholic and HCV group [median (95% C.I.): 42.6 (36.5-48.8) vs 38.6 (31.2-45.9) months; p = 0.756]. Conclusions: Alcoholic patients present with a more compromised liver function and a more advanced HCC, less frequently detected during surveillance. Nevertheless, alcoholic etiology per se does not affect survival as compared with HCV-related cases, since it was similar in the two groups once adjusted for the confounding factors. http://dx.doi.org/10.1016/j.dld.2015.01.119
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FIRST STEPS TOWARDS UNDERSTANDING THE DYNAMIC EVOLUTION OF GUT MICROBIOTA IN DIFFERENT STAGES OF LIVER DISEASE
PREVALENCE OF HEPATITIS E IN TERTIARY HOSPITAL CENTRE IN NORTHERN ITALY
F.R. Ponziani 1 , S. Pecere 1 , F. Paroni Sterbini 2 , V. Petito 1 , M. Siciliano 1 , T. Di Rienzo 1 , A. Palladini 2 , D. Zambrano 1 , F. Franceschi 1 , E. Gaetani 1 , F. Scaldaferri 1 , L. Masucci 2 , M. Sanguinetti 2 , A. Gasbarrini 1 1 Internal Medicine Department, Gastroenterology Division, Catholic University Of Sacred Heart of Rome, Rome, Italy 2 Microbiology Department, Catholic University Of Sacred Heart of Rome, Rome, Italy
INTRODUCTION: Liver cirrhosis is associated to intestinal barrier derangement and dysbiosis. AIM: To preliminary describe gut microbiota modifications in a population of Italian patients with liver cirrhosis. PATIENTS AND METHODS: Fecal samples were collected in 13 cirrhotic patients and 10 healthy controls, no exposed for at least one month to antibiotics, prebiotics, probiotics and bowel colonoscopy preparation. Gut microbiota composition was assessed by a metagenomic gene-targeted approach (16S rRNA), following DNA isolation from stool samples stored at–80 ◦ C. Data were analyzed in Qiime. Non parametric tests were used for the final statistical analysis. RESULTS: The enterotypification of the 23 subjects was comparable to that of the Western general population, with a prevalence of Bacteroides (enterotype 1, 77%, often overlapping with enterotype 3, 18%) with no inter- or intra-group differences between cirrhotics and healthy controls. A trend toward an unbalance between the Firmicutes to Bacteroidetes ratio was found throughout the different Child Pugh stages (close to 1 in Child A, reduced to half in Child B and to ¼ in Child C p = 0.081). Compared to healthy individuals, cirrhotics microbiota was more enriched in Bacilli (Lactobacillaceae, Streptococcaceae, Enterococcaceae; p = 0.001), especially in case of intermediate stage liver disease (abundance in Child B patients 48.6%; p = 0.008). Clostridia (Clostridiaceae, Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Clostridiaceae, Peptostreptococcaceae, Peptococcaceae) were the most abundant in the initial phases of the disease (62.3% in Child A patients p = 0.06). Patients with at least one clinical sign of decompensation lost the relative abundance of Clostridia (abundance 62.3% in compensated patients vs 20.8% in decompensated ones vs 35.4% in healthy controls p = 0.04). CONCLUSION: Liver cirrhosis is a fascinating model of gut microbiota modifications, that are connected with the progression of liver impairment. http://dx.doi.org/10.1016/j.dld.2015.01.115
e53
V. Zuccaro 1 , P. Columpsi 1 , S. Paolucci 2 , M. Mariani 1 , S. Toppino 1 , A. Malfitano 1 , A. Parisi 1 , S.F.A. Patruno 1 , F. Baldanti 2 , R. Bruno 1 1 Department of Infectious Diseases–IRCCS San Matteo - University of Pavia, Pavia, Italy 2 Virology Unit IRCCS San Matteo - University of Pavia, Pavia, Italy
Introduction: In developed countries, hepatitis E is a zoonosis usually caused by the genotypes 3 and 4. In Italy the prevalence of anti-HEV is 1-5% among the healthy population. A large prospective study has shown that HEV accounts for approximately 10% of acute non A, non B hepatitis cases in Italy. Aim: The aim of the study was to evaluate the prevalence of hepatitis E among patients admitted to the Division of Infectious and tropical Disease for acute hepatitis without evidence of autoimmunity and antibody against HAV-HBV-HCV. Materials and Methods Results: A total of 970 patients were admitted to Division of Tropical and Infectious Diseases from 2013 to 2014. Among them 27 had acute hepatitis and 3 (11%) were positive for hepatitis E. All were anti-HEV IgM and IgG positive and were also positive for HEV-RNA, viral genotype was 3 subtype F in all cases. All HEV patients were living from Pavia and denied having travelled abroad. Diagnosis of hepatitis E was based on the presence of IgM anti-HEV and confirmed by the detection of HEVRNA - RTPCR on patients samples. Viral isolates were sequenced to characterize subtypes. Two cases with acute disease had a selflimited course with AST-ALT normalization within 3-6 weeks. One patient died from acute on chronic liver disease. All cases showed high level of amylases during the acute phase. Conclusions: This is the first report of hepatitis E in the Pavia area and it confirms the increasing trend of prevalence of autochthonous hepatitis E in our country. The increased prevalence might be related either to the spread of the HEV virus in our country and to the implementation of HEV screening in patients with acute hepatitis. In the case of acute hepatitis with high amylases level should prompt exclude HEV infection. http://dx.doi.org/10.1016/j.dld.2015.01.116 F-23 IMPACT OF RIFAXIMIN IN THE PREVENTION OF BACTERIAL INFECTIONS IN CIRRHOSIS M. Mariani 1 , L. Scudeller 2 , S.F.A. Patruno 1 , V. Zuccaro 1 , P. Columpsi 1 , S. Toppino 1 , A. Malfitano 1 , A. Parisi 1 , G. Filice 1 , R. Bruno 1 1
Division of Infectious and Tropical Diseases–IRCCS San Matteo - University of Pavia, Pavia, Italy 2 Scientific Direction, IRCCS Policlinico San Matteo, Pavia, Italy Background and aims: Infectious events represent a leading factor able to accelerate the progression from compensated to decompensated stage of cirrhosis, with a subsequent worsening of the prognosis. Due to the high frequency of infectious complications in cirrhotic patients, a great effort was made in order to improve the survival rate. Rifaximin was advanced as a possible primary prophylactic therapy against spontaneous bacterial infections. We retrospectively investigated the role of this antibiotic in
e54
Abstracts / Digestive and Liver Disease 47S (2015) e43–e66
reducing the proportion of infected patients in treated and nontreated groups. Methods: We enrolled 649 patients whose clinical and personal data, prescribed therapy, microbiological findings and laboratory tests were collected from previous discharge letters and our institution database. We excluded patients with ACLF and acute hepatitis. Aetiology, drug resistance and site of infection were collected as well. Results: Risk of developing bacterial infections was significantly lower in patients treated with rifaximin (6 month of treatment, 10 days per month, 400gr t.i.d.) (OR 0.29; 95% CI 0.20-0.40, p < 0.001) compared to those not treated. Moreover, in our cohort we find out a prevalence of infections sustained by Gram-positive bacteria (61.5% of isolations). Conclusions: Rifaximin continuous treatment turned out to be a very effective factor involved in bacterial infections prevention in cirrhotic patients. Our study showed a shift in general bacterial prevalence among pathogens to Gram positive, this finding should be considered as well before administering an empirical therapy in cirrhotic patients. http://dx.doi.org/10.1016/j.dld.2015.01.117 F-24 SERUM ALPHA-FETOPROTEIN MODIFICATION (DELTA-AFP) IS A HIGHLY SPECIFIC TOOL TO SUSPECT HCC RECURRENCE AFTER LIVER TRANSPLANTATION F.R. Ponziani 1,∗ , S. Bhoori 1 , M. Bongini 1 , M. Flores 1 , C. Muscarà 1 , V. Mazzaferro 1 1 Liver Transplant, Hepatobiliary and Gastrointestinal Surgery, Hepatology National Cancer Insitute of Milan, Milan, Italy
Introduction: Alpha-fetoprotein (AFP) is the main tumor marker of hepatocellular carcinoma (HCC). Despite AFP values at listing have been used to predict HCC recurrence after liver transplantation (LT), its role in patients’ surveillance after LT has not been established yet. Aim: To investigate the usefulness of serum AFP modification to suspect recurrence in patients who previously underwent LT for HCC. Materials and Methods Results: We investigated all consecutive patients undergoing LT for HCC within Milan or up-to-seven criteria from January 2004 to December 2013. Serum AFP was collected at the time of LT and every 6-months for 2 years and every year thereafter. Patients surveillance consisted in semiannual abdominal ultrasound or CT scan for the first 5-years, then every year. 231 LT recipients were investigated (median age 61 (14-64), 89% males, 30% HBV, 51.5% HCV, 4% coinfected, 10% alcohol, 8% other, 4% HIV); 31 of them (13%) experienced HCC recurrence. Among HCC recurrence-free patients, 24 (10%) developed cirrhosis or liver failure, severe hepatitis or alcohol abuse during follow-up; since their median AFP values had higher peaks, they were excluded to avoid biases. Univariate analysis failed to demonstrate any association between serum AFP at any timepoint and HCC recurrence, while its modification (difference between the highest AFP value detected during follow-up or the value detected at recurrence, and the lowest serum AFP value, named “delta-AFP”) was strongly associated with HCC recurrence (p < 0.0001). Multivariable analysis confirmed delta-AFP as the only independent predictive factor of HCC recurrence (OR 1.28, 95%CI 1.116, 1.470; p = 0.001). The accuracy of delta-AFP in predicting recurrence was 71.5% (95%CI
65% > 77.5%), with the best identified cut-off value of 6.57 ng/ml (sensitivity 61.3% specificity 100%, NPV 96% PPV 100%). Conclusions: Delta-AFP is a very easy-to-use and highly specific tool to suspect HCC recurrence after LT. http://dx.doi.org/10.1016/j.dld.2015.01.118 F-25 CLINICAL PRESENTATION, TREATMENT AND OUTCOME OF ALCOHOL- AND HEPATITIS C VIRUS- RELATED HEPATOCELLULAR CARCINOMA IN THE NEW CENTURY: COMPARISON BEFORE AND AFTER ADJUSTMENT WITH PROPENSITY SCORE ANALYSIS L. Bucci 1 , F. Garuti 1 , V. Camelli 1 , B. Lenzi 1 , M. Bernardi 1 , F. Trevisani 1 , for the Italian Liver Cancer (ITA.LI.CA) group 1 Dipartimento di Scienze Mediche e Chirurgiche Alma Mate Studiorum - University of Bologna, Bologna, Italy
Introduction and aims: Hepatitis C virus (HCV) and alcohol abuse are the main causes of hepatocellular carcinoma (HCC) in Western world, accounting for about 60% and 20% of cases, respectively. This study aimed at comparing the clinical presentation and outcome of alcohol- and HCV- related HCC diagnosed in the new century. Materials and Methods: 1844 HCV and 636 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC from January 2000 to December 2012 were compared for age, gender, type of diagnosis, Barcelona Clinic Liver Cancer (BCLC), tumor gross pathology, portal vein thrombosis (PVT), esophageal varices, model for end stage liver disease (MELD), Child-Pugh class, alpha-fetoprotein (AFP), treatment and survival. For survival analysis, a propensity matching model was performed to minimize imbalances of prognostic factors between groups. Results: Underlying cirrhosis was present in 96% of both alcoholic and HCV patients. Alcoholic patients were significantly younger and more likely male, diagnosed with a tumor outside surveillance, in intermediate and terminal BCLC stage and in a worse hepatic function setting. Consequently, the overall survival was decreased in alcoholic compared to HCV patients [median (95% C.I.): 34.5 (28.7-40.2) vs 43.6 (40.9-46.3) months; p < 0.001]. A one-to-one matching after propensity score adjustment according to age, gender, type of diagnosis, BCLC stage, tumor gross pathology, PVT and treatment was performed. This analysis selected 354 patients per group, well balanced for baseline prognostic factors. The overall survival did not differ any longer between alcoholic and HCV group [median (95% C.I.): 42.6 (36.5-48.8) vs 38.6 (31.2-45.9) months; p = 0.756]. Conclusions: Alcoholic patients present with a more compromised liver function and a more advanced HCC, less frequently detected during surveillance. Nevertheless, alcoholic etiology per se does not affect survival as compared with HCV-related cases, since it was similar in the two groups once adjusted for the confounding factors. http://dx.doi.org/10.1016/j.dld.2015.01.119