Variants of CARD15 are associated with an aggressive clinical course of Crohn's Disease. An IG-IBD Study

Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation.We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives.Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unre…

Characteristics of patients with hepatitis C virus-related chronic liver diseases just before the era of oral direct-acting antiviral therapy in Italy

Background In 2017, oral direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection became available free of charge for all HCV-RNA-positive patients, irrespective of their fibrosis stage. Aim The aim of this study was to evaluate the characteristics of HCV-related chronic liver disease (CLD) in Italy just before the introduction of DAA therapy. Patients and methods Patients with CLD were enrolled in two national surveys conducted in 2001 and in 2014. The two surveys prospectively enrolled patients aged older than 18 years referring to Italian liver units throughout the country using a similar clinical approach and analytical methods. Results Out of the 12 564 patie…

HCV genotype 1a and 1b: Similarities and differences in clinical features, therapeutic outcome and predictors of response

The burden of HBV infection in HCV patients in Italy and the risk of reactivation under DAA therapy

Background: There is increasing awareness of HBV reactivation in HCV-RNA-positive/HBV-coinfected patients with chronic liver disease (CLD) treated with oral direct-acting antivirals (DAAs). Aim: To provide figures on the prevalence of HBV markers in HCV-RNA-positive subjects in Italy, where these findings are lacking. Methods: All subjects aged ≥18 years with CLD consecutively referring to Italian liver units located throughout country were prospectively enrolled in two national surveys in 2001 and 2014. Results: The total number of HCV-RNA-positive cases was 6984; 356 (5.1%) subjects vaccinated against HBV were excluded. A total of 6628 cases were evaluated. The prevalence rates of HBsAg, …

Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes

BackgroundHepatitis C virus (HCV) infects approximately 3% of the world population and is the leading cause of liver disease, impacting hepatocyte metabolism, depending on virus genotype. Hepatic metabolic functions show rhythmic fluctuations with 24-h periodicity (circadian), driven by molecular clockworks ticking through translational-transcriptional feedback loops, operated by a set of genes, called clock genes, encoding circadian proteins. Disruption of biologic clocks is implicated in a variety of disorders including fatty liver disease, obesity and diabetes. The relation between HCV replication and the circadian clock is unknown.MethodsWe investigated the relationship between HCV core…

Etiological factors of chronic hepatitis in Italy: a 2014 national survey.

Background The last Italian prevalence survey on chronic hepatitis (CH) conducted in 2001 showed that the hepatitis C virus (HCV) was the main agent associated with CH. Aim The aim of this study was to evaluate epidemiological changes in CH occurring after 13 years. Patients and methods Enrollment of 1392 CH consecutive patients referred to 16 Italian liver units in 2014 scattered all over the country (four in the North, four in the Center, four in the South, and four in the Islands) was performed. Results The mean age of the patients was 58.3 years, with a sex ratio (male/female) of 1.5. HCV infection (also with other etiologies) continues to be the most prevalent etiology (58.1%). However…

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

Viral clearance in HCV viraemic patients with normal alanine aminotransferase after combination therapy: a controlled, open-labelled study

Summary Background : In patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels, liver fibrosis has been reported in 0–22% of cases and advanced liver disease in 5–10% of cases. Aim : To determine whether patients with persistently normal alanine aminotransferase levels clear infection after anti-viral therapy at equal or different rates from infected patients with raised alanine aminotransferase levels. Methods : Thirty-five hepatitis C virus RNA-positive patients with fibrosis at liver histology (Group 1) were matched for genotype, sex, age and histology with patients with raised alanine aminotransferase levels (Group 2). Both groups were …

P621 Efficacy and safety of golimumab in ulcerative colitis. Preliminary data from a multicenter Italian study

Experts' opinions on the role of liver biopsy in HCV infection: A Delphi survey by the Italian Association of Hospital Gastroenterologists (A.I.G.O.)

Background/Aims: Liver biopsy represents the gold standard to establish a diagnosis in all liver patients, but its current position in chronic viral hepatitis is questioned. We aimed to create a consensus on best practice of use of liver biopsy in the management of chronic HCV infection. Methods: We applied the Delphi method to 12 clinical scenarios of chronic HCV infection, to assess the extent of agreement (consensus measurement) and to resolve disagreement (consensus development) on the appropriateness of liver biopsy. Results: Among 108 chosen hepatologists, 61 (56.5%) accepted to participate to the first-round survey. In four patients the majority of experts (from 61.4 to 86.2%) agreed…

Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48-week treatment. Patients (n_696) received peginterferon alfa-2a, 180 mg/week, or peginterferon alfa-2b, 1.5 mg/kg/week, plus ribavirin, 1000-1200 mg/day, for 48 weeks (standard, n _237) or for 24, 48, or 72 weeks if HCV-RNA–negative at weeks 4, 8, or 12, respectively (variable, n _ 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8-51.4] of the patients in the standard group and in 48.8% (CI 44.2-53.3) of the patients in the variable group (P _ 0.37). The percentages of …

Forecasting liver disease burden

Modeling interactions between Human Equilibrative Nucleoside Transporter-1 and other factors involved in the response to gemcitabine treatment to predict clinical outcomes in pancreatic ductal adenocarcinoma patients.

Background Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, characterized by largely unsatisfactory responses to the currently available therapeutic strategies. In this study we evaluated the expression of genes involved in gemcitabine uptake in a selected cohort of patients with PDAC, with well-defined clinical-pathological features. Methods mRNA levels of hENT1, CHOP, MRP1 and DCK were evaluated by means of qRT-PCR in matched pairs of tumor and adjacent normal tissue samples collected from PDAC patients treated with gemcitabine after surgical tumor resection. To detect possible interaction between gene expression levels and to identify subgroups of patients a…

Gender differences in chronic liver diseases in two cohorts of 2001 and 2014 in Italy

Background: Gender differences in chronic liver disease (CLD) have been partially investigated. To extend the present knowledge, we evaluated 12,263 patients with CLD enrolled in two national surveys (9997 in 2001 and 2557 in 2014). Methods: The two surveys prospectively recruited patients aged ≥ 18 referring to Italian liver units throughout the country using a similar clinical approach and analytical methods. Results: The overall male to female ratio (M/F) was 1.4 (7138/5124). Compared with females, males were significantly more likely to be younger (52.9 vs. 58.7 yrs.), with HBV infection alone (13.2% vs. 9.2%) and with alcoholic liver disease alone (11.4% vs. 6.9%), but less likely t…

Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3.

The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established.Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weightor75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration.At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treat…

Characteristics of hepatocellular carcinoma in Italy.

This study aimed to assess the main features of hepatocellular carcinoma at the time of diagnosis in Italy, particularly in relation to the presence or absence of underlying cirrhosis, hepatitis virus marker patterns, age of the subjects and alpha-foetoprotein values.A total of 1148 patients with hepatocellular carcinoma seen at 14 Italian hospitals in the 1-year period from May 1996 to May 1997 were the subjects of this prevalence study. Both newly diagnosed cases (incident cases) and cases diagnosed before May 1996 but still attending the hospitals during the study period (prevalent cases) were included.We found that 71.1% of cases were positive for hepatitis C virus antibodies but negati…

Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data.

Background and aims: Retreatment with a combination of α interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. Methods: To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000–1200 mg/daily depending on body weight) was given for 24–60 (mean 39.5) weeks. Results: Biochemical …

Gross Pathologic Types of Hepatocellular Carcinoma in Italy

The prevalence and independent predictors of the different macroscopic types of hepatocellular carcinoma (HCC) were assessed in 1,073 unselected patients of 14 hospitals in Italy from May 1996 to May 1997. Solitary HCC was the most common cancer type (44.6%), followed by multinodular (44.2%), diffuse (8.4%) and massive (2.8%) types. After adjustment for the influence of confounders by multiple logistic regression analysis, Child-Pugh grades B and C were found to be independent predictors of multinodular (odds ratio, OR, 2.0; 95% confidence interval (CI) = 1.5–2.6) and diffuse (OR 2.6; 95% CI = 1.6–4.4) HCC types. These findings indicate that the majority of HCC cases are not detected at a p…

Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV aetiology

Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent associated with liver cirrhosis in Italy. Abstract BACKGROUND: Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent associated with liver cirrhosis in Italy. AIM: To assess epidemiological, laboratory and clinical features of liver cirrhosis in Italy in 2014. PATIENTS: Out of the 2557 consecutive subjects evaluated in 16 hospitals located throughout Italy in 2014, 832 (32.6%) had liver cirrhosis and were enrolled in this study. RESULTS: The mean age of subjects was 60.3years, with a male/female ratio of 1.7; 74.9% of cases had Child…

Anticardiolipin antibodies in patients with liver disease.

OBJECTIVE: Our aim was to test the hypothesis that anticardiolipin antibodies (aCL) may cause an antiphospholipid syndrome and thrombotic events in patients with liver disease. METHODS: aCL were measured in 116 healthy controls and 372 patients with liver disease of different stage and etiology: 136 cases secondary to hepatitis C virus (HCV) infection, 139 due to hepatitis B virus (HBV) infection, 69 with alcoholic liver damage, and 28 cryptogenic in origin. Prior thrombotic events were recorded. The results were related to age, gender, stage, severity, and etiology of the liver disease, as well as to the occurrence of organ- and nonorgan-specific autoantibodies. RESULTS: aCL were positive …

ROLE OF NAKED CUTICLE HOMOLOG 1 GENE ON CHR 16Q12 IN INFLAMMATORY BOWEL DISEASE.

Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to Peg-interferon alpha-2a and ribavirin

Guidelines for the treatment of patients infected with hepatitis C virus of genotypes 2 and 3 (HCV-2 and HCV-3, respectively) recommend a 24-week course of Peg-interferon (Peg-IFN) alpha-2a combined with ribavirin, despite 50% of patients in registration trials attaining a sustained virologic response (SVR) following Peg-IFN alpha-2a monotherapy. The aim of this study was to delineate patient characteristics that might help to identify individuals likely to benefit from ribavirin discontinuation. One hundred and forty-four HCV-2- and HCV-3-infected patients initiated Peg-IFN alpha-2a (180 microg/week) and ribavirin (1000 or 1200 mg/day); those with viral clearance at week 4 were randomized …

Neoadjuvant Chemo-Radiotherapy for Patients with Borderline Resectable Pancreatic Cancer: A Meta-Analytical Evaluation of Prospective Studies

Context For patients with borderline resectable pancreatic cancer, the benefit of neoadjuvant therapy remains to be defined. Objective We did a systematic search of the literature on this topic. Methods Prospective studies, where chemotherapy, irrespective of regimen, in combination with radiotherapy was given before surgery to patients with borderline resectable cancer, were analyzed by a meta-analytical method. Primary outcome was tumor response; surgical exploration rate, resection rate, therapy-induced toxicity, and survival were secondary outcomes. Data were expressed as weighted pooled proportions with 95% confidence interval (95% CI). Results Eleven studies with 247 participants were…

Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: A meta-analysis

Efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin of non-responders to standard or pegylated IFN plus ribavirin has been assessed in various studies, but sustained virologic response (SVR) rates are variable and factors influencing efficacy and tolerability still remain incompletely defined. We aimed to focus on SVR rates and to identify factors influencing them in this meta-analysis.MEDLINE as well as a manual search were used. Studies were included if they were controlled or uncontrolled trials, if they had been published as full-length papers and if they included non-responders to standard or pegylated IFN and ribavirin therapy. Fourteen trials were included in t…

Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis.

Objectives To assess the evidence for tobacco smoking as a risk factor for the causation of chronic pancreatitis. Methods We performed a meta-analysis with random-effects models to estimate pooled relative risks (RRs) of chronic pancreatitis for current, former, and ever smokers, in comparison to never smokers. We also performed dose-response, heterogeneity, publication bias, and sensitivity analyses. Results Ten case-control studies and 2 cohort studies that evaluated, overall, 1705 patients with chronic pancreatitis satisfied the inclusion criteria. When contrasted to never smokers, the pooled risk estimates for current smokers was 2.8 (95% confidence interval [CI], 1.8-4.2) overall and 2…

Combination therapy with amantadine and interferon in naı̈ve patients with chronic hepatitis C: meta-analysis of individual patient data from six clinical trials

Abstract Background/Aims In chronic hepatitis C, clinical trials evaluating the efficacy of amantadine (AMA) and interferon (INF) compared to INF monotherapy, have produced conflicting results. We performed a meta-analysis of the individual patient's data from previous studies. Methods Nine hundred and seventy-two patients from six European centres were evaluated by means of individual patient meta-analysis, using mixed models with centres and the centre–treatment interaction fitted as random variables. Results At the end of therapy, virological responses were 38.5% (95% CI 34.1–42.8) after INF and AMA, and 29.5% (95% CI 25.5–33.6) after INF alone (P=0.003). Sustained response occurred in 1…

Severe reduction of blood lysosomal acid lipase activity in cryptogenic cirrhosis: A nationwide multicentre cohort study

Background and aims Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis. Methods This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2. Results Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic …

Identification of Naïve Hcv-1 Patients with Chronic Hepatitis who may Benefit from Dual Therapy with Peg-Interferon and Ribavirin.

Background & Aims The pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified. Methods In 1045 patients treated with peg-interferon and ribavirin, two therapeutic strategies were confronted: the first one evaluated only baseline variables associated with sustained virological response (SVR), and the second one included the rapid virologic response (RVR) in addition to baseline predictors. An 80% SVR rate was the threshold to retain a strategy as clinically relevant. Results Overall, 414 patients (39.6%) attained SVR. In the first strategy, the hierarchy of features independently associated with SVR was IL28B CC genotype (OR 5.082; CI 3.637…

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds…

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference.

Abstract Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent …

Variation in genes encoding for interferon λ-3 and λ-4 in the prediction of HCV-1 treatment-induced viral clearance

Background & Aims In patients with chronic HCV-1 infection, recent evidences indicate that determination of a dinucleotide polymorphism (ss469415590, ΔG/TT) of a new gene, designated IFN λ-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sustained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. Results In the study cohort of 539 pa…

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C.

none 29 no Background: Aim was to select naïve patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon. +. ribavirin therapy. Methods: In 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort). Results: In the derivation cohort, 257 achieved rapid virological response and 8…

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 77…

HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome.

Aim: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA).Patients and methods: A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13 %) with subtype 1a and 1,074 (87 %) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype.Results: At multivariate analysis, baseline characteristics differentiating patients …

The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy.

BACKGROUND We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naive to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One…

Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials.

Radiofrequency thermal ablation (RF) and percutaneous ethanol injection (PEI) have been employed in the treatment of small hepatocellular carcinoma (HCC) as curative treatments. The aim of the study was to review the available evidence comparing RF to PEI for small HCC.Cochrane, MEDLINE, CANCERLIT, and ENBASE databases were used.randomized clinical trials evaluating RF vs. PEI. Data were extracted from each randomized controlled trial (RCT). Primary outcomes were overall survival and local recurrence. Meta-analysis software was used and risk differences (RDs) and their 95% confidence intervals and Q-test for heterogeneity were calculated.Five RCTs were identified including 701 patients. The…

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

Background The joint effect of the interaction of alcohol intake, hepatitis B virus (HBV) and hepatitis C virus (HCV) on the risk of cirrhosis is still unexplored because a large sample size is required for this investigation. Objective Evaluation of interaction of HBV, HCV and alcohol abuse on the risk of cirrhosis. Design We analysed 12,262 consecutive patients with chronic liver disease of various aetiologies referring to 95 Italian liver units in 2001 or 2014. To evaluate the interaction between alcohol abuse, HBV infection, and HCV infection, patients unexposed to either factors were used as reference category. Adjustment for BMI and age was done by multiple logistic regression analysi…

Influence of universal HBV vaccination on chronic HBV infection in Italy: Results of a cross-sectional multicenter study

Background and Aim The universal hepatitis B vaccination for infants and 12-year-old adolescents (the latter limited to the first 12 years of application) was launched in Italy in 1991. Twenty-three years later we evaluated the impact of the vaccination campaign on the burden of HBsAg-positive chronic liver diseases (CLD). Material and Methods 513 HBsAg-positive chronic carriers referring to 16 Italian liver units were investigated and compared with HBsAg carriers enrolled in previous surveys. Results The proportion of inactive carriers decreased from 20.0% in 2001 to 3.3% in 2014, while that of cirrhotic patients increased from 22.6 to 33.2%. Regarding the age class 0–33 (fully covered by …