Health related quality of life in chronic liver diseases.

BACKGROUND & AIMS: The impact of chronic liver diseases (CLDs) on health-related quality of life (HRQoL) is relevant to understand the burden of these conditions and inform decision-making processes related to their care. Studies simultaneously comparing the HRQoL of patients affected by the major CLDs to that of the general population are still lacking and are the subject of this study. METHODS: Using the EQ-5D-3L questionnaire, we analysed and compared HRQoL data from 2962 Italian patients affected by CLDs and forming a representative sample of the general Italian population (6800 individuals). Exploratory analyses were conducted to investigate the effects of each CLD on HRQoL, using the general population as reference and adjusting for possible confounders. RESULTS: Patients with CLDs (HBV, HCV, PSC, PBC, AIH, NAFLD/NASH) in the chronic hepatitis stage and with compensated cirrhosis (CC) showed HRQoL similar to the general population. However, AIH were more likely to report problems in self-care and lower EQ-5D VAS score, while NAFLD/NASH and HCV showed an increased risk of anxiety/depression. On the other hand, with progression to more advanced stages of liver disease (DC or HCC), HRQoL decreased significantly with higher risk of reporting problems in the physical domains, and significant reductions in the VAS and utility index scores. CONCLUSIONS: Different subtypes of CLD affected different QoL domains. This study therefore provides a real estimate of the impact of CLDs on patients' HRQoL, and represents a much needed tool to inform decision-making while assessing the effectiveness and cost-effectiveness of the care of these patients.

Clinical outcome indicators in chronic hepatitis B and C: A primer for value-based medicine in hepatology.

BACKGROUND & AIMS: Chronic liver diseases (CLDs) are major health problems that require complex and costly treatments. Liver-specific clinical outcome indicators (COIs) able to assist both clinicians and administrators in improving the value of care are presently lacking. The Value-Based Medicine in Hepatology (VBMH) study aims to fill this gap, devising and testing a set of COIs for CLD, that could be easily collected during clinical practice. Here we report the COIs generated and recorded for patients with HBV or HCV infection at different stages of the disease. METHODS/RESULTS: In the first phase of VBMH study, COIs were identified, based on current international guidelines and literature, using a modified Delphi method and a RAND 9-point appropriateness scale. In the second phase, COIs were tested in an observational, longitudinal, prospective, multicentre study based in Lombardy, Italy. Eighteen COIs were identified for HBV and HCV patients. Patients with CLD secondary to HBV (547) or HCV (1391) were enrolled over an 18-month period and followed for a median of 4 years. The estimation of the proposed COIs was feasible in the real-word clinical practice and COI values compared well with literature data. Further, the COIs were able to capture the impact of new effective treatments like direct-acting antivirals (DAAs) in the clinical practice. CONCLUSIONS: The COIs efficiently measured clinical outcomes at different stages of CLDs. While specific clinical practice settings and related healthcare systems may modify their implementation, these indicators will represent an important component of the tools for a value-based approach in hepatology and will positively affect care delivery.

Diagnostic Value of Quantitative Perfusion Computed Tomography Technique in the Assessment of Tumor Response to Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

AIM: The aim of this study was to assess the role of dynamic contrast-enhanced perfusion computed tomography (pCT) imaging in the early detection of blood flow changes related to antiangiogenic treatment with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), being the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria the standard of reference. METHODS: Between 2012 and 2016, 43 cirrhotic patients (male, n = 39; female, n = 4) with biopsy-proven multifocal HCC underwent multi-detector-row computed tomography, and pCT examinations were performed before and every 2 months after sorafenib administration. Perfusion CT technique is based on the acquisition of 16 dynamic slices/scan per 40 scans, performed on a 256-slice multi-detector-row computed tomography scanner, after intravenous bolus injection of 50 mL of iodinated contrast agent (350 mg I/mL) at a flow rate of 5 mL/s. According to mRECIST, patients were stratified into complete (CR) or partial response (PR) and stable (SD) or progressive disease (PD). The following pCT parameters were calculated: hepatic perfusion (mL/s per 100 g), time to peak (seconds), arterial perfusion (mL/s), and hepatic perfusion index (%). Perfusion CT values at baseline and first follow-up were reported for all mRECIST groups and then compared between the nonprogressor (CR, PR, SD) and progressor groups (PD). RESULTS: Most pCT values were significantly higher (P < 0.01) between baseline and follow-up in the CR and PR groups, whereas nonsignificant differences were found among SD patients, and a nonsignificant trend (P > 0.05) toward increase was observed among PD patients. Moreover, pCT values were significantly higher (P = 0.05) at baseline in the nonprogressor group compared with the progressor. CONCLUSION: Preliminary results suggest that pCT adds quantitative data of vascularization, thus demonstrating its usefulness in the assessment of therapeutic response to sorafenib in advanced HCC, in line with mRECIST criteria, offering 1-step information on tissue cellularity and vascularization.

Optimising the clinical strategy for autoimmune liver diseases: Principles of value-based medicine.

BACKGROUND: Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy. METHODS: In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset. RESULTS: Two-hundred fourteen patients were enrolled and followed-up for a median time of 54months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies. CONCLUSIONS: We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Direct-acting antivirals combination for elderly patients with chronic hepatitis C: A cost-effectiveness analysis.

BACKGROUND: Chronic hepatitis C (CHC) has been undertreated among elderly patients. Interferon-free treatment represents an opportunity for these patients. The aim of this study was to assess the cost-effectiveness of directly acting antivirals (DAAs) in CHC elderly patients. METHODS: A Markov model of CHC natural history was built. This study focuses on CHC patients older than 65 years, stratified according to genotype (1/4, 2 and 3), liver fibrosis (METAVIR F1 to F4), age and frailty phenotype (robust, pre-frail and frail). DAAs combination vs no treatment was simulated for each theoretical population, assessing life years, quality-adjusted life years (QALYs), costs, incremental cost-effectiveness ratios (ICERs) in a lifetime time horizon and by the Healthcare System perspective. RESULTS: Incremental cost-effectiveness ratio increased with age and frailty status in all fibrosis stages. For robust F3 and F4 patients ICERs remained below the willingness-to-pay threshold (WTP) of 40 000€/QALY up to age 75 and 86 years, respectively, depending on drug price and sustained virological response probability (sensitivity analysis). Notably, in F4 and frail subjects older than 75 years, ICER was more sensitive to non-liver-related mortality rate. In elderly F1 and F2 patients, ICERs were below WTP only up to 77 years old, with wide variability among frailty phenotypes. CONCLUSIONS: Cost-effectiveness of DAAs treatment of elderly CHC patients is solid in those with advanced fibrosis, but it depends strongly on frailty status and age, particularly in patients with milder fibrosis stages. Accurate assessment of clinical variables, including frailty, is necessary to allocate limited resources to this special population.

Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib.

UNLABELLED: Mutations in polycystins are a cause of polycystic liver disease. In polycystin-2 (PC2)-defective mice, cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent activation of the Rat Sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen signal-regulated kinase-extracellular signal-regulated kinase (ERK) 1/2 pathway stimulates the growth of liver cysts. To test the hypothesis that sorafenib, a Raf inhibitor used for the treatment of liver and kidney cancers, inhibits liver cyst growth in PC2-defective mice, we treated PC2 (i.e., Pkd2(flox/-) :pCxCreER(TM) [Pkd2cKO]) mice with sorafenib-tosylate for 8 weeks (20-60 mg/kg/day). Sorafenib caused an unexpected increase in liver cyst area, cell proliferation (Ki67), and expression of phosphorylated ERK (pERK) compared with Pkd2cKO mice treated with vehicle. When given to epithelial cells isolated from liver cysts of Pkd2cKO mice (Pkd2cKO-cells), sorafenib progressively stimulated pERK1/2 and cell proliferation [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assay (MTS)] at doses between 0.001 and 1 µM; however, both pERK1/2 and cell proliferation significantly decreased at the dose of 10 µM. Raf kinase activity assay showed that whereas B-Raf is inhibited by sorafenib in both wild-type (WT) and Pkd2cKO cells, Raf-1 is inhibited in WT cells but is significantly stimulated in Pkd2cKO cells. In Pkd2cKO cells pretreated with the PKA inhibitor 14-22 amide, myristolated (1 µM) and in mice treated with octreotide in combination with sorafenib, the paradoxical activation of Raf/ERK1/2 was abolished, and cyst growth was inhibited. CONCLUSION: In PC2-defective cells, sorafenib inhibits B-Raf but paradoxically activates Raf-1, resulting in increased ERK1/2 phosphorylation, cell proliferation, and cyst growth in vivo. These effects are consistent with the ability of Raf inhibitors to transactivate Raf-1 when a PKA-activated Ras promotes Raf-1/B-Raf heterodimerization, and are inhibited by interfering with cAMP/PKA signaling both in vitro and in vivo, as shown by the reduction of liver cysts in mice treated with combined octreotide and sorafenib.

ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice.

BACKGROUND & AIMS: Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts. METHODS: We studied mice in which Pkd1 or Pkd2 were conditionally inactivated following exposure to tamoxifen; these mice were called Pkd1(flox/-):pCxCreER (Pkd1KO) and Pkd2(flox/-):pCxCreER (Pkd2KO). RESULTS: Pkd1KO and Pkd2KO mice developed liver defects; their LCECs expressed VEGF, VEGFR-2, hypoxia-inducible factor (HIF)-1alpha, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and proliferating cell nuclear antigen (PCNA). In Pkd2KO but not Pkd1KO mice, exposure to the VEGFR-2 inhibitor SU5416 significantly reduced liver cyst development, liver/body weight ratio, and expression of pERK and PCNA. VEGF secretion and phosphorylation of ERK1/2 and VEGFR-2 were significantly increased in cultured LCECs from Pkd2KO compared with Pkd1KO mice. Inhibition of protein kinase A (PKA) reduced VEGF secretion and pERK1/2 expression. Addition of VEGF to LCECs from Pkd2KO mice increased phosphorylated VEGFR-2 and phosphorylated mitogen signal-regulated kinase (MEK) expression and induced phosphorylation of ERK1/2; this was inhibited by SU5416. Expression of HIF-1alpha increased in parallel with secretion of VEGF following LCEC stimulation. VEGF-induced cell proliferation was inhibited by the MEK inhibitor U1026 and by ERK1/2 small interfering RNA. CONCLUSIONS: The PKA-ERK1/2-VEGF signaling pathway promotes growth of liver cysts in mice. In Pkd2-defective LCECs, PKA-dependent ERK1/2 signaling controls HIF-1alpha-dependent VEGF secretion and VEGFR-2 signaling. Autocrine and paracrine VEGF signaling promotes the growth of liver cysts in Pkd2KO mice. VEGF inhibitors might be used to treat patients with polycystic liver disease.

Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice.

UNLABELLED: Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1alpha)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1alpha, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1alpha accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026. CONCLUSION: These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation.

Radioembolization vs sorafenib in locally advanced hepatocellular carcinoma with portal vein tumor thrombosis: A propensity score and Bayesian analysis.

OBJECTIVE: In this study we aimed to compare patient outcomes between the use of transarterial radioembolization (TARE) and sorafenib in patients with hepatocellular carcinoma (HCC) and intrahepatic portal vein tumor thrombosis (PVTT). METHODS: A total of 65 patients with HCC and intrahepatic PVTT treated in five Italian hospitals between 2012 and 2018 were included in the analysis. Those with any previous treatment, extension of PVTT to the main portal tract and extrahepatic involvement were excluded. Propensity score matching analysis and Bayesian model averaging analysis were performed. RESULTS: Of the 41 patients treated with TARE and 24 with sorafenib, 11 patients were downstaged to curative-intent surgery (liver transplant in three and hepatectomy in eight), including 10 treated with TARE and one with sorafenib. TARE was more effective than sorafenib in downstaging patients to surgery, achieving a mean survival of 54 months. In the 54 patients without downstaging after treatment, of whom 31 were treated with TARE and 23 with sorafenib, median survival was 20.3 and 9.1 months, respectively (P = 0.001), with different 1-, 2- and 3-year OS rates (64.5%, 42.6% and 37.3% vs 39.1%, 13.0% and 0%). Both propensity score and Bayesian model averaging confirmed an improvement in overall survival in the TARE group compared with sorafenib treatment. CONCLUSIONS: TARE was more effective than sorafenib in downstaging patients with HCC to surgery, providing a significant improvement in survival. Even in patients who were not downstaged to surgery, survival appeared to be superior with TARE over sorafenib.

Connections between genetics and clinical data: Role of MCP-1, CFTR, and SPINK-1 in the setting of acute, acute recurrent, and chronic pancreatitis.

OBJECTIVES: Acute, acute recurrent, and chronic pancreatitis are inflammatory diseases with multifactorial pathogenic mechanisms. Genetic mutations and polymorphisms have been correlated with pancreatitis. The aim of this study was to investigate the association of cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor Kazal type 1 (SPINK-1) gene mutations and monocyte chemoattractant protein 1 (MCP-1) -2518A/G polymorphism with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis (CP), and to associate genetic backgrounds with clinical phenotype in these three conditions. METHODS: One hundred eighteen AP, 64 ARP, 142 CP patients, and 88 normal controls were enrolled consecutively. We analyzed MCP-1 serum levels using enzyme-linked immunosorbent assay. Polymorphism -2518 of MCP-1 and SPINK-1 N34S gene mutations were determined by PCR-restriction-fragment length polymorphism. Sequence analysis was performed when necessary. Thirty-three CFTR mutations were analyzed in CP and ARP patients using multiplex DNA testing. RESULTS: Serum MCP-1 levels were significantly higher in all patients affected by pancreatic inflammatory diseases. Moreover, we found a significant over-representation of the MCP-1G allele in ARP patients. We found a statistically significant association of CFTR gene mutations with ARP, but not with CP. We did not find a statistically significant association of ARP or CP with the N34S SPINK-1 gene mutation. Interestingly, 39 of 64 ARP patients (61%) carried at least one genetic mutation and/or polymorphism. Five of 64 ARP patients had pancreas divisum and four of these five also carried the G allele. CONCLUSIONS: Analysis of a comprehensive range of potential susceptibility variants is needed to support modeling of the effects of genes and environment in pancreatitis. As such, beyond gene mutations, the context within which those mutations exist must be considered. In pancreatitis the context includes the inflammatory response, clinical features, and exogenous factors.

Dynamic contrast enhanced perfusion CT imaging: A diagnostic biomarker tool for survival prediction of tumour response to antiangiogenetic treatment in patients with advanced HCC lesions.

PURPOSE: To investigate whether perfusion-CT (p-CT) imaging could depict the inhibition of tumor neoangiogenesis induced by Sorafenib in advanced hepatocellular carcinoma (HCC), and whether it could be useful in predicting survival during treatment. MATERIALS AND METHODS: Ninety-eight p-CT examinations were performed among 29 cirrhotic patients, with advanced HCC, before and every 2 months after Sorafenib administration, on a 256-slice MDCT scanner. Perfusion parameters were considered and statistically compared, at baseline and follow-up, between non-progressor (complete response, stable disease or partial response) and progressor (progressive disease) group. Kaplan-Meier analyses estimated the time-to-survival in overall population, after stratifying patients according to mRECIST. RESULTS: The group that responded to Sorafenib showed a significant reduction of values in HCC target lesions after anti-angiogenic therapy (p < 0.01), in comparison with progressor group that demonstrated an increase or no significant variation. When patients were stratified into mRECIST, higher survival rate was observed in the non-progressor group compared to the progressor (48.6% vs 28.6%), and statistically significant correlation (p=0.01) was found between percentage variation of perfusion parameters, from baseline to follow-up, and overall survival rate. CONCLUSION: Quantitative analysis of perfusion parameters, represents prognostic indicators useful in assessment of response to anti-angiogenic therapy, allowing for optimization of individualized treatment.

Diagnostic value of dynamic contrast-enhanced CT with perfusion imaging in the quantitative assessment of tumor response to sorafenib in patients with advanced hepatocellular carcinoma: A feasibility study.

PURPOSE: To investigate the feasibility of perfusion-CT (p-CT) measurements in quantitative assessment of hemodynamic changes related to sorafenib in patients with advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-two patients with advanced HCC underwent p-CT study (256-MDCT scanner) before and 2 months after sorafenib administration. Dedicated perfusion software generated a quantitative map of arterial and portal perfusion and calculated the following perfusion parameters in target liver lesion: hepatic perfusion (HP), time-to-peak (TTP), blood volume (BV), arterial perfusion (AP), and hepatic perfusion index (HPI). After the follow-up scan, patients were categorized as responders and non-responders, according to mRECIST. Perfusion values were analyzed and compared in HCC lesions and in the cirrhotic parenchyma (n=22), such as between baseline and follow-up in progressors and non-progressors. RESULTS: Before treatment, all mean perfusion values were significantly higher in HCC lesions than in the cirrhotic parenchyma (HP 47.8±17.2 vs 13.3±6.3mL/s per 100g; AP 47.9±18.1 vs 12.9±10.7mL/s; p<0.001). The group that responded to sorafenib (n=17) showed a significant reduction of values in HCC target lesions after therapy (HP 29.2±23.3 vs 48.1±15.1; AP 29.4±24.6 vs 49.2±17.4; p<0.01), in comparison with the non-responder group (n=5) that demonstrated no significant variation before and after treatment of HP (46.9±25.1 vs 46.7±24.1) and AP (43.4±21.7 vs 43.5±24.6). Among the responder group, HP percentage variation (Δ) in target lesions, during treatment, showed a significantly different (p=0.04) ΔHP in the group with complete response (79%) compared to the group with partial response or stable disease (16%). CONCLUSIONS: p-CT technique can be used for HCC quantitative assessment of changes related to anti-angiogenic therapy. Identification of response predictors might help clinicians in selection of patients who may benefit from targeted-therapy allowing for optimization of individualized treatment.

Liver-allocation policies for patients affected by HCC in Europe.

The main goal of organ allocation systems is to guarantee an equal access to the limited resource of liver grafts for every patients on the waiting list, balancing between the ethical principles of equity, utility, benefit, need, and fairness. The European heath care scenario is very complex, as it is essentially decentralized and each Nation and Regions inside the nation, operate on a significant degree of autonomy. Furthermore the epidemiology of liver diseases and HCC, which is different among European countries, clearly inpacts on indications and priorities. The aims of this review are to analyze liver allocation policies for hepatocellular carcinoma, among different European. The European area considered for this analysis included 5 macro-areas or countries, which have similar policies for liver sharing and allocation: Centro Nazionale Trapianti (CNT) in Italy; Eurotransplant (Germany, the Netherlands, Belgium, Luxembourg, Austria, Hungary, Slovenia, and Croatia); Organizacion Nacional de Transplantes (ONT) in Spain; Etablissement français des Greffes (EfG) in France; NHS Blood & Transplant (NHSBT) in the United Kingdom and Ireland; Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland). Each identified area, as network for organ sharing in Europe, adopts an allocation system based either on a policy center oriented or on a policy patient oriented. Priorization of patients affected by HCC in the waiting list for deceased donors liver transplant worldwide is dominated by 2 main principles: urgency and utility. Despite the absence of a common organs allocation policy over the Eurpean countries, long-term survival patients listed for transplant due to HCC are comparable to the long-term survival reported in the UNOS register. However, as the principles of allocation are being re-discussed and new proposals emerge, and the epidemiology of liver disease changes, an effort toward a common system is highly advisable.