Markus Peck-Radosavljevic

The burden of liver disease in Europe. A review of available epidemiological data.

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation

The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbetas role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.

Effect of Everolimus on Survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib The EVOLVE-1 Randomized Clinical Trial

IMPORTANCE Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01035229.

Meta‐analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis

This meta‐analysis aims to compare the diagnostic performance of acoustic radiation force impulse (ARFI) elastography and transient elastography (TE) in the assessment of liver fibrosis using liver biopsy (LB) as ‘gold‐standard’.

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial

BACKGROUND Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. METHODS We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). FINDINGS Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. INTERPRETATION Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. FUNDING Gilead Sciences.

Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt

Background: In patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), prognostic scores may identify those with a poor prognosis or even those with a clear survival benefit. The Child-Pugh score (CPS) is well established but several drawbacks have led to development of the model of end stage liver disease (MELD). Aim: The aim of the study was to compare the predictive power of CPS and MELD, to validate the original MELD formula, and to assess the predictive value of the determinants used in the two prognostic scores outside of a study setting. Patients: A total of 501 patients underwent elective TIPS placement and 475 patients fulfilled the inclusion criteria. Methods: Data of all patients undergoing elective TIPS in one university hospital and four community hospitals in Vienna, Austria, between 1991 and 2001, were analysed retrospectively. The main statistical tests were Cox proportional hazards regression model, the log rank test, Kaplan-Meier analysis, and concordance c statistics. Results: Median follow up was 5.2 years and median survival was 4.6 years. During follow up, 230 patients died, 75 within three months after TIPS placement. In stepwise proportional hazards analyses, independent predictors of death were creatinine level, bilirubin level, age, and refractory ascites. MELD was better in predicting survival in a stepwise Cox model but both scores were equally predictive in c statistics for one month, three month, and one year survival. Renal function was the strongest independent predictor of survival. Conclusions: Although MELD was the primary predictor of overall survival in multivariate analysis, c statistics showed that both scores can be used for patients undergoing TIPS with equal accuracy. For assessing prognosis in patients undergoing TIPS implantation, there seems little reason to replace the well established Child-Pugh score.

Platelet Count/Spleen Diameter Ratio for the Noninvasive Diagnosis of Esophageal Varices: Results of a Multicenter, Prospective, Validation Study

BACKGROUND AND AIMS:Noninvasive assessment of esophageal varices (EV) may improve the management of patients with cirrhosis and decrease both the medical and financial burden related to screening. In this multicenter, international study, our aim was to prospectively validate the use of the platelet count/spleen diameter ratio for the noninvasive diagnosis of EV.METHODS:A total of 218 cirrhotic patients underwent screening endoscopy for EV. Platelet count/spleen diameter ratio ((N/mm3)/mm) was assessed in all patients and its diagnostic accuracy was calculated. On the basis of previous results, a platelet count/spleen diameter ratio cutoff of 909 was applied to this population. The diagnostic accuracy of the platelet count/spleen diameter ratio was further evaluated for both severity and etiology of disease subgroups.RESULTS:Prevalence of EV was 54.1%. The platelet count/spleen diameter ratio had 86.0% (95% CI, 80.7–90.4%) diagnostic accuracy for EV, which was significantly greater as compared with either accuracy of platelet count alone (83.6%, 95% CI 78.0–88.3%, P = 0.038) or spleen diameter alone (80.2%, 95% CI 74.3–85.3%, P = 0.018). The 909 cutoff had 91.5% sensitivity (95% CI 85.0–95.9%), 67.0% specificity (95% CI 56.9–76.1%), 76.6% positive predictive value, 87.0% negative predictive value, 2.77 positive likelihood ratio, and 0.13 negative likelihood ratio for the diagnosis of EV. Accuracy of the platelet count/spleen diameter ratio was maintained for both severity and etiology of disease subgroups.CONCLUSIONS:The platelet count/spleen diameter ratio may be proposed as a safe and reproducible means to improve the management of cirrhotic patients who should undergo screening endoscopy for EV.

Sorafenib in Unresectable Hepatocellular Carcinoma from Mild to Advanced Stage Liver Cirrhosis

BACKGROUND Few data are available on the safety and efficacy of sorafenib in patients with multifocal hepatocellular carcinoma (HCC) and advanced liver cirrhosis. METHODS Between May 2006 and December 2007, we treated 59 patients (Child-Pugh class A/B/C, 26/23/10) with unresectable HCC with sorafenib (daily target dose, 400 mg twice daily). Data were collected retrospectively. Survival curves were calculated via the Kaplan-Meier method. RESULTS One patient (Child-Pugh class B) had a partial response, 14 patients (Child-Pugh class A/B/C, 5/7/2) had stable disease, and 32 patients (Child-Pugh class A/B/C, 15/11/6) had progressive disease; 12 patients were not evaluable because they had no follow-up radiologic evaluation. In the intention-to-treat group, the median time to progression and overall survival (OS) time were 2.8 months (range, 1.4-6.5 months) and 6.5 months (range, 0.4-17.4 months), respectively. Well-preserved liver function and lower Barcelona Clinic Liver Cancer stage were associated with a longer OS time on univariate analysis. There were four severe gastrointestinal bleedings (grade 4-5; Child-Pugh class B/C, 2/2). Most drug-related side effects were low grade and manageable irrespective of liver function. CONCLUSIONS Sorafenib is effective and safe in patients with multifocal HCC and Child-Pugh class A cirrhosis. Survival in Child-Pugh class B patients is significantly less than in Child-Pugh class A patients, warranting a prospective randomized trial with a placebo group. Child-Pugh class C patients have a limited life expectancy despite sorafenib treatment because of their severe underlying disease and derive little benefit from sorafenib treatment.

Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver

BACKGROUND/AIMS Thrombocytopenia secondary to cirrhosis of the liver and portal hypertension is a well-known complication of advanced stage liver disease, but theories about the underlying pathogenetic mechanisms, mostly centering on splenic sequestration and destruction of platelets, have failed to solve the problem so far. METHODS Peripheral platelet count and thrombopoietin levels in human plasma were measured in 28 patients with cirrhosis of the liver. Seven of those patients underwent orthotopic liver transplantation and five patients portal decompression by transjugular intrahepatic portosystemic shunt. Thrombopoietin plasma levels were followed for 14 days after the interventions. RESULTS No measurable thrombopoietin was detectable in the plasma of 28 thrombocytopenic patients with cirrhosis of the liver, in contrast to thrombocytopenic patients without liver disease. Seven of these patients with cirrhosis underwent orthotopic liver transplantation, resulting in a rise of thrombopoietin levels within 2 days after transplantation. The rise in platelet number followed with a mean lag of 6 days, and shortly thereafter, thrombopoietin levels returned to levels below the limit of detection. Five patients with thrombocytopenia, who underwent only decompression of portal hypertension, showed no rise in either thrombopoietin levels or platelet count. CONCLUSIONS Thrombocytopenia associated with liver disease may at least in part be attributable to inadequate thrombopoietin production in the failing liver.

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol

Objective Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥20% or to values <12 mm Hg). Design Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80–160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25–50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. Results 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): −19±10% versus −12±11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. Conclusions Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.