- Email: [email protected]
Increased Plasma Levels of Von Willebrand Factor and Factor VIII (FVIII) During Acute Bacterial Infection Drive a Pro-Hemostatic Imbalance and Herald Severe Outcome in Cirrhosis
POSTER PRESENTATIONS Results: According to the OGTT, 91 (74.5%) were dysglycaemic, including 38 (31.1%) with diabetes and 53 (43.4%) with prediabetes. The prevalence of diabetes was the lowest in Child-Turcotte-Pugh class B (23.1%) as compared to class A (37%) and class C (38.5%). The overall dysglcaemic state follows a similar pattern with class B being the lowest at 71.2% and class A and C, 74.1% and 79.5% respectively. The ADA recommended threshold HbA1c value of ≥48 mmol/mol (6.5%) had a sensitivity and specificity of 82.5% and 91.4% respectively for determining the presence of diabetes. The prevalence of anaemia was very high (77 %) in our study. The sensitivity of HbA1c was lesser (72%) in anaemic patients as compared to non-anaemic ones (92.3%). However, the specificity was comparable at 89.4% in anaemic and 93.3% in non-anaemic patients. Sensitivity decreased with increasing severity of anaemia, being 80% in mild and 71% in severe anaemia. Specificity on the other hand remained almost constant. Conclusions: The extremely high prevalence of diabetes reported in the study reiterates the need for mandatory testing in chronic liver disease patients. HbA1c, a very convenient test, shows high sensitivity and specificity even in the presence of anaemia in liver disease. This can be utilised for screening purposes in chronic liver disease patients. THU-397 LIVER CIRRHOSIS IS CHARACTERIZED BY AN ACQUIRED LYSOSOMAL ACID LIPASE DEFICIENCY INDEPENDENT FROM THE ETIOLOGY OF LIVER DISEASE U. Vespasiani-Gentilucci1, P. Gallo1, A. Porcari1, F. Vorini1, L. Piccioni2, G. Galati1, A. De Vincentis1, C. Dell’Unto1, F. Piemonte3, G. Tozzi3, E. Riva2, A. Picardi1. 1Internal Medicine and Hepatology; 2Virology, University Campus Bio-Medico of Rome; 3Neuroscience and Neurorehabilitation, Bambino Gesù Pediatric Hospital, Rome, Italy E-mail: [email protected] Background and Aims: Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disease with an almost absent LAL activity, characterized by massive microvesicular steatosis evolving to cirrhosis and liver failure. Milder reductions in LAL function have been recently described in patients with NAFLD. We aimed to determine LAL activity, and to investigate the most common single nucleotide polymorphism (SNP) affecting the LIPA gene and responsible for >50% of LAL-D cases (rs116928232 c.894G > A), in a population of patients with cryptogenic cirrhosis. Methods: Consecutive patients with cryptogenic cirrhosis were enrolled. Two control groups were selected: cirrhotics of known etiology; healthy subjects undergoing medicine check-ups. LAL activity was dosed with dried-blood technique using the inhibitor Lalistat-2. The c.894G > A mutation was analyzed in subjects with a reduced LAL activity (<0.8 nmol/spot/h) by pyrosequencing method in SNP mode. Results: Sixty patients with cryptogenic cirrhosis, 80 cirrhotics from other etiology (HCV: 45; alcohol: 23; HBV: 7; autoimmune: 5), and 80 healthy subjects were enrolled. Patients with cryptogenic cirrhosis had a mean BMI of 31.1 ± 7.9 kg/m2 and a high prevalence of diabetes (66%), consistent with a prevalent metabolic etiology. LAL activity was strongly reduced in patients with cryptogenic cirrhosis with respect to healthy subjects (0.64 ± 0.29 Vs 1.05 ± 0.42 nmol/spot/h, p < 0.001), but similarly reduced also in cirrhotics of other etiology (0.63 ± 0.33 nmol/spot/h; p < 0.001 Vs healthy subjects; p = 0.5 Vs cryptogenic cirrhotics). None of the subjects with reduced LAL activity carried the c.894G > A SNP but one patient with HCV cirrhosis. In the entire cirrhotic group, LAL activity was not correlated with age, sex, or Child-Pugh class, but directly correlated with platelet number (rho = 0.43; p < 0.001), and inversely with spleen volume (cm2) (rho = −0.22; p = 0.01) and presence of oesophageal varices (rho = −0.19; p < 0.05). Conclusions: Liver cirrhosis of any etiology is characterized by an acquired deficiency of LAL activity that is not tightly dependent on liver function, is associated with surrogate indices of portal hypertension, and the determinants of which need to be investigated. S290
The impaired LAL function is possibly implicated in the progression of liver damage and in the severe alterations of cholesterol metabolism characterizing cirrhosis (cellular membrane stability; biliary acid and sex hormone metabolism, etc.). THU-398 EFFECTIVENESS OF BETA-BLOCKERS IN PRIMARY PREVENTION OF BLEEDING: A COMPARISON OF PROPRANOL VS. CARVEDILOL BY HVPG V. Calvaruso1, A. Bonaccorso1, F. Simone1, G. Butera1, V. Di Marco1, A. Craxì1, P.L. Almasio1. 1DIBIMIS, University of Palermo, Palermo, Italy E-mail: [email protected] Background and Aims: Portal hypertension is a clinical syndrome defined by a pathological increase of the Hepatic Venous Pressure Gradient (HVPG) above 5 mmHg. Beta-blockers (BB) are recommended for primary prophylaxis of variceal bleeding in patients with cirrhosis. However, only 30% of patients reduce HVPG under BB. To assess the reduction of HVPG under BB in patients with cirrhosis of various etiologies undergoing primary prophylaxis of portal hypertensive bleeding (PHB), in order to compare the efficacy of propranolol vs. carvedilol and to analyze the outcome of cirrhosis. Methods: Consecutive patients with cirrhosis (1.2009 to 3.2015, X HCV, y HBV, y etoh, x NASH), with large varices (> or 0 F2), with no history of previous bleeding were included. After measuring baseline HVPG, all received incremental propranolol or carvedilol to achieve a hearth rate of 55/min. After 3 months, HVPG was repeated to assess response (<12 mmHg or > or =20% reduction). Band ligation was performed in HVPG nonresponders. All patients were followed for at least 6 months after baseline HVPG. Results: Seventy patients (age 60.1 ± 10, males 69%) were eligible, and 35 (50%) responded to BB (9 patients, 26%, on propranolol and 26, 74%, on carvedilol; p = 0.001). HVPG at 3 months was significantly reduced from baseline in patients on carvedilol (Δ −3.2 mmHg p < 0.001) but not in those on propranolol (delta – 1.8 mmHg, p = 0.089). Patients not reducing HVPG on BB were significantly older than those who reduced (0.026), had higher ferritin ( p = 0.048), and had more frequent ascites ( p = 0.008). During a median follow-up of 42 months (range 6–80) disease events related to portal hypertension (PHB; de novo ascites) occurred in 18 of the 50 (36%) patients without ascites at baseline. Fifteen patients (21.4%) developed hepatocellular carcinoma, and 16 (23%) died during the observation period. Responders to BB had a lower rate of liver decompensation compared to nonresponders (26% vs 50%, p = 0.02). Baseline HVPG (HR 1.2, p 0.048) and ascites at baseline (HR 4.16, p = 0.003) were associated to a higher likelihood of death. Conclusions: High HVPG at baseline segregates a group of cirrhotics with a worse prognosis. In our cohort, carvedilol reduced HVPG more effectively than propranolol. A hemodynamic response to a BB was associated with a lesser occurence of PHB and ascites. THU-399 INCREASED PLASMA LEVELS OF VON WILLEBRAND FACTOR AND FACTOR VIII (FVIII) DURING ACUTE BACTERIAL INFECTION DRIVE A PRO-HEMOSTATIC IMBALANCE AND HERALD SEVERE OUTCOME IN CIRRHOSIS V. La Mura1,2, A. Tripodi3, G. Tosetti4, V. Chantarangkul3, L. Baronciani3, F. Peyvandi3, M. Iavarone2, A. Sangiovanni5, M. Primignani5, M. Colombo2. 1Internal Medicine, Biomedical Science for Health, IRCCS, San Donato, University of Milan; 2Division of Gastroenterology and Hepatology, IRCCS Ca’ Granda Maggiore Hospital Foundation, University of Milan; 3Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, University of Milan and IRCCS Ca’ Granda Maggiore Hospital Foundation; 4Division of Gastroenterology and Hepatology, IRCCS Ca’ Granda Maggiore Hospital Foundation, University of Milan; 5Division of Gastroenterology and Hepatology, University of Milan and IRCCS Ca’ Granda Maggiore Hospital Foundation, Milan, Italy E-mail: [email protected]
Journal of Hepatology 2016 vol. 64 | S213–S424
POSTER PRESENTATIONS Background and Aims: Plasma levels of Von Willebrand factor (VWF) are increased in cirrhotics with endotoxemia, severe portal hypertension, liver dysfunction, and independently predict clinical outcome. Acute bacterial infections, a life threatening complication of cirrhosis, further contributes to increase VWF, whose impact on the hemostatic balance has never been addressed by ad hoc clinical studies. We wondered whether acute bacterial infections may lead to a pro-hemostatic imbalance in cirrhosis that worsens prognosis. Methods: We prospectively collected clinical and laboratory data of 83 patients hospitalized for decompensated cirrhosis and screened for acute bacterial infection. Baseline examinations included the main pro-(FVIII) and anti-coagulants (antithrombin, AT, protein C, PC), VWF, d-dimer, and Factor II (FII). Endogenous Thrombin Potential (ETP) allowed testing for the in vitro thrombin generation in plateletpoor plasma and thromboelastography to assess for whole blood hypercoagulability. Intra-hospital mortality and complications such as organ dysfunction were collected. Results: There were 54 infected and 29 infection-free patients, the mean MELD score was 18.6 ± 6.8 vs 15.0 ± 5.9 ( p = 0.018), and the VWF 627 ± 329 vs 436 ± 152 (p = 0.003), respectively. Infection was associated with high levels of FVIII, d-dimer and low levels of AT, PC, FII. By multivariable analysis FVIII ( p = 0.031) and VWF ( p = 0.023) were associated with infection, independently of MELD. In infected patients VWF levels correlated with FVIII (R = 0.658, p < 0.001), significantly influencing in vitro hypercoagulability when measured by thromboelastography (high maximum clot firmness, MCF, low clotting formation time, CFT, p < 0.05), not by ETP. These results suggest a pro-hemostatic imbalance involving pro- and anticoagulant factors and platelets. During hospitalization, 24 patients experienced a complication, 10 of them died, MELD score being a strong predictor of outcome. Interestingly, high levels of FVIII significantly increased the risk of severe outcome as predicted by MELD ( p = 0.005) in association with a pro-hemostatic imbalance measured by thromboelastography. Conclusions: Acute bacterial infections lead to increased plasma levels of VWF and FVIII that drive a pro-hemosttaic imbalance resulting in worsened prognosis in cirrhotic patients. THU-400 CRITICAL ROLE OF HEPATOCYTE DEATH IN THE PATHOPHYSIOLOGY OF ACUTE ON CHRONIC LIVER FAILURE: ASSOCIATION BETWEEN THE EXTENT OF HEPATOCYTE DEATH AND TYPES OF PRECIPITATING EVENT Z. Cao1, Y. Wang1, L. Chen1, X. Xiang1, Y. Liu1, J. Lu1, L. Lin1, Q. Xie1, H. Wang1. 1Department of infectious diseases, Rui-Jin hospital affiliated to Shanghai Jiao-Tong University School of medicine, Shanghai, China E-mail: [email protected] Background and Aims: Acute on chronic liver failure (ACLF) usually develops from a precipitating event on the basis of established cirrhosis. Current pathophysiological hypothesis for ACLF is that precipitating events may primarily cause acute liver injury, subsequently trigger inflammation response and eventually lead to multiple organ failures. The aim of the study was to investigate the role of hepatocytes death in such process. Methods: 66 ACLF patients were identified from a prospective cohort of 117 patients with acute decompensated cirrhosis (ADC) admitted to Rui-Jin hospital from February 2013 to August 2014. 50 healthy volunteers (HC) and 50 patients with compensated cirrhosis (CC) were enrolled as controls. Precipitating events were categorized into hepatic alone, extra-hepatic alone and mixed events (hepatic and extra-hepatic). Hepatocyte death was assessed by the serological measurements of cell death biomarkers, M30-antigen (hepatocytes apoptosis) and M65-antigen (hepatocytes total death). Results: Among those with ACLF, 18 were precipitated by hepatic event alone (Hepatic-ACLF), 19 by extra-hepatic event alone (Extrahepatic-ACLF) and 23 by both hepatic and extra-hepatic events (Mixed-ACLF). Another 6 had no obvious precipitating event.
Median serum M30-antigen in ACLF was 10.5-fold ( p < 0.001), 2.6fold ( p < 0.001), and 1.7-fold ( p < 0.001) higher than in HC, CC and ADC. Serum M65-antigen in HBV-ACLF was 31.5-fold ( p < 0.001), 3.3fold ( p < 0.001), and 3.2-fold (p < 0.001) higher than in HC, CC and ADC. Both M30- and M65-antigen significantly correlated with the severity scores of cirrhosis, CTP (both p < 0.001) and MELD (both p < 0.001). ROC analysis revealed that both serum M30-antigen (AUC 0.71, p < 0.001) and M65-antigen (AUC 0.78, p < 0.001) could well discriminate ACLF from ADC. Mixed-ACLF demonstrates the highest level of serum hepatocytes death (M30: 19.6-fold of HC, M65: 85.9-fold of HC) followed by that from Hepatic-ACLF (M30: 9.8-fold of HC, M65: 32.2-fold of HC) and Extrahepatic-ACLF (M30: 5.6-fold of HC, M65: 16.8-fold of HC). Serum M30- and M65-antigen from Extrahepatic-ACLF was relatively low and even close to that from ADC (M30: 6.2-fold of HC, M65: 9.9-fold of HC). Conclusions: Markedly elevated hepatocyte death is crucial for the development of ACLF. Hepatic rather than extra-hepatic precipitating event is the primary reason for massive hepatocyte death. However, extra-hepatic injury may help exaggerating the extent of hepatocyte death in ACLF.
Clinical trials in progress THU-480 MULTICENTRIC PROSPECTIVE STUDY OF VALIDATION OF ANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATED WITH SORAFENIB. INNOVATE STUDY A.C. Gardini1, L. Faloppi2, B. Daniele3, G.F. Foschi4, S. Cascinu5, G. Marisi1, G. Masi6, L. Chessa7, F. Negri8, E. Scarpi1, D. Santini9, J. Corbelli10, N. Silvestris11, E. Tamburini12, V. Zagonel13, M. Scartozzi2. 1 IRST-IRCCS, Forli; 2University of Cagliari, Cagliari; 3Ospedale Rummo, Benevento; 4Interne Medicine, Faenza; 5University of Modena, Modena; 6 University of Pisa, Pisa; 7Dipartimento Scienze Mediche “Mario Aresu”, Cagliari; 8University of Parma, Parma; 9Policlinico Universitario Campus Bio-Medico, Roma; 10Oncology Unit, Faenza; 11Oncologico Bari, Bari; 12 Oncologia Rimini, Rimini; 13IOV Veneto, Padova, Italy E-mail: [email protected] Background and Aims: Preclinical data suggested that significant HCC growth is dependent on angiogenesis, and an increase in tumour dimension may induce vascular endothelial cell proliferation. SNPs in VEGF,VEGFR,HIF1α, angiopoietin2 and eNOS genes have also been correlated to tumour neoangiogenesis through different biological mechanisms. In the ALICE-2 study patients (PT) receiving sorafenib were tested for HIF-1α,VEGF-A and VEGF-C SNPs. At multivariate analysis rs12434438 of HIF-1α,rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors for PFS and OS. At the combined analysis of significant SNPs the presence of 2 favourable alleles of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0.0001) and OS (respectively: 19.0 vs 13.5 vs 7.5 months; p < 0.0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α)select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs(PFS: 2.6 months,p < 0.0001; OS:6.6 months,p < 0.0001). In ePHAS study PT homozygous for a specific haplotype (Ht1:T-4b at eNOS-786/eNOS VNTR) showed a lower median PFS(2.1vs6.2 months, p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)compared to other genotypes. The multivariate analysis confirmed specific haplotype as the only independent prognostic factor.
Journal of Hepatology 2016 vol. 64 | S213–S424
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The impaired LAL function is possibly implicated in the progression of liver damage and in the severe alterations of cholesterol metabolism characterizing cirrhosis (cellular membrane stability; biliary acid and sex hormone metabolism, etc.). THU-398 EFFECTIVENESS OF BETA-BLOCKERS IN PRIMARY PREVENTION OF BLEEDING: A COMPARISON OF PROPRANOL VS. CARVEDILOL BY HVPG V. Calvaruso1, A. Bonaccorso1, F. Simone1, G. Butera1, V. Di Marco1, A. Craxì1, P.L. Almasio1. 1DIBIMIS, University of Palermo, Palermo, Italy E-mail: [email protected] Background and Aims: Portal hypertension is a clinical syndrome defined by a pathological increase of the Hepatic Venous Pressure Gradient (HVPG) above 5 mmHg. Beta-blockers (BB) are recommended for primary prophylaxis of variceal bleeding in patients with cirrhosis. However, only 30% of patients reduce HVPG under BB. To assess the reduction of HVPG under BB in patients with cirrhosis of various etiologies undergoing primary prophylaxis of portal hypertensive bleeding (PHB), in order to compare the efficacy of propranolol vs. carvedilol and to analyze the outcome of cirrhosis. Methods: Consecutive patients with cirrhosis (1.2009 to 3.2015, X HCV, y HBV, y etoh, x NASH), with large varices (> or 0 F2), with no history of previous bleeding were included. After measuring baseline HVPG, all received incremental propranolol or carvedilol to achieve a hearth rate of 55/min. After 3 months, HVPG was repeated to assess response (<12 mmHg or > or =20% reduction). Band ligation was performed in HVPG nonresponders. All patients were followed for at least 6 months after baseline HVPG. Results: Seventy patients (age 60.1 ± 10, males 69%) were eligible, and 35 (50%) responded to BB (9 patients, 26%, on propranolol and 26, 74%, on carvedilol; p = 0.001). HVPG at 3 months was significantly reduced from baseline in patients on carvedilol (Δ −3.2 mmHg p < 0.001) but not in those on propranolol (delta – 1.8 mmHg, p = 0.089). Patients not reducing HVPG on BB were significantly older than those who reduced (0.026), had higher ferritin ( p = 0.048), and had more frequent ascites ( p = 0.008). During a median follow-up of 42 months (range 6–80) disease events related to portal hypertension (PHB; de novo ascites) occurred in 18 of the 50 (36%) patients without ascites at baseline. Fifteen patients (21.4%) developed hepatocellular carcinoma, and 16 (23%) died during the observation period. Responders to BB had a lower rate of liver decompensation compared to nonresponders (26% vs 50%, p = 0.02). Baseline HVPG (HR 1.2, p 0.048) and ascites at baseline (HR 4.16, p = 0.003) were associated to a higher likelihood of death. Conclusions: High HVPG at baseline segregates a group of cirrhotics with a worse prognosis. In our cohort, carvedilol reduced HVPG more effectively than propranolol. A hemodynamic response to a BB was associated with a lesser occurence of PHB and ascites. THU-399 INCREASED PLASMA LEVELS OF VON WILLEBRAND FACTOR AND FACTOR VIII (FVIII) DURING ACUTE BACTERIAL INFECTION DRIVE A PRO-HEMOSTATIC IMBALANCE AND HERALD SEVERE OUTCOME IN CIRRHOSIS V. La Mura1,2, A. Tripodi3, G. Tosetti4, V. Chantarangkul3, L. Baronciani3, F. Peyvandi3, M. Iavarone2, A. Sangiovanni5, M. Primignani5, M. Colombo2. 1Internal Medicine, Biomedical Science for Health, IRCCS, San Donato, University of Milan; 2Division of Gastroenterology and Hepatology, IRCCS Ca’ Granda Maggiore Hospital Foundation, University of Milan; 3Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, University of Milan and IRCCS Ca’ Granda Maggiore Hospital Foundation; 4Division of Gastroenterology and Hepatology, IRCCS Ca’ Granda Maggiore Hospital Foundation, University of Milan; 5Division of Gastroenterology and Hepatology, University of Milan and IRCCS Ca’ Granda Maggiore Hospital Foundation, Milan, Italy E-mail: [email protected]
Journal of Hepatology 2016 vol. 64 | S213–S424
POSTER PRESENTATIONS Background and Aims: Plasma levels of Von Willebrand factor (VWF) are increased in cirrhotics with endotoxemia, severe portal hypertension, liver dysfunction, and independently predict clinical outcome. Acute bacterial infections, a life threatening complication of cirrhosis, further contributes to increase VWF, whose impact on the hemostatic balance has never been addressed by ad hoc clinical studies. We wondered whether acute bacterial infections may lead to a pro-hemostatic imbalance in cirrhosis that worsens prognosis. Methods: We prospectively collected clinical and laboratory data of 83 patients hospitalized for decompensated cirrhosis and screened for acute bacterial infection. Baseline examinations included the main pro-(FVIII) and anti-coagulants (antithrombin, AT, protein C, PC), VWF, d-dimer, and Factor II (FII). Endogenous Thrombin Potential (ETP) allowed testing for the in vitro thrombin generation in plateletpoor plasma and thromboelastography to assess for whole blood hypercoagulability. Intra-hospital mortality and complications such as organ dysfunction were collected. Results: There were 54 infected and 29 infection-free patients, the mean MELD score was 18.6 ± 6.8 vs 15.0 ± 5.9 ( p = 0.018), and the VWF 627 ± 329 vs 436 ± 152 (p = 0.003), respectively. Infection was associated with high levels of FVIII, d-dimer and low levels of AT, PC, FII. By multivariable analysis FVIII ( p = 0.031) and VWF ( p = 0.023) were associated with infection, independently of MELD. In infected patients VWF levels correlated with FVIII (R = 0.658, p < 0.001), significantly influencing in vitro hypercoagulability when measured by thromboelastography (high maximum clot firmness, MCF, low clotting formation time, CFT, p < 0.05), not by ETP. These results suggest a pro-hemostatic imbalance involving pro- and anticoagulant factors and platelets. During hospitalization, 24 patients experienced a complication, 10 of them died, MELD score being a strong predictor of outcome. Interestingly, high levels of FVIII significantly increased the risk of severe outcome as predicted by MELD ( p = 0.005) in association with a pro-hemostatic imbalance measured by thromboelastography. Conclusions: Acute bacterial infections lead to increased plasma levels of VWF and FVIII that drive a pro-hemosttaic imbalance resulting in worsened prognosis in cirrhotic patients. THU-400 CRITICAL ROLE OF HEPATOCYTE DEATH IN THE PATHOPHYSIOLOGY OF ACUTE ON CHRONIC LIVER FAILURE: ASSOCIATION BETWEEN THE EXTENT OF HEPATOCYTE DEATH AND TYPES OF PRECIPITATING EVENT Z. Cao1, Y. Wang1, L. Chen1, X. Xiang1, Y. Liu1, J. Lu1, L. Lin1, Q. Xie1, H. Wang1. 1Department of infectious diseases, Rui-Jin hospital affiliated to Shanghai Jiao-Tong University School of medicine, Shanghai, China E-mail: [email protected] Background and Aims: Acute on chronic liver failure (ACLF) usually develops from a precipitating event on the basis of established cirrhosis. Current pathophysiological hypothesis for ACLF is that precipitating events may primarily cause acute liver injury, subsequently trigger inflammation response and eventually lead to multiple organ failures. The aim of the study was to investigate the role of hepatocytes death in such process. Methods: 66 ACLF patients were identified from a prospective cohort of 117 patients with acute decompensated cirrhosis (ADC) admitted to Rui-Jin hospital from February 2013 to August 2014. 50 healthy volunteers (HC) and 50 patients with compensated cirrhosis (CC) were enrolled as controls. Precipitating events were categorized into hepatic alone, extra-hepatic alone and mixed events (hepatic and extra-hepatic). Hepatocyte death was assessed by the serological measurements of cell death biomarkers, M30-antigen (hepatocytes apoptosis) and M65-antigen (hepatocytes total death). Results: Among those with ACLF, 18 were precipitated by hepatic event alone (Hepatic-ACLF), 19 by extra-hepatic event alone (Extrahepatic-ACLF) and 23 by both hepatic and extra-hepatic events (Mixed-ACLF). Another 6 had no obvious precipitating event.
Median serum M30-antigen in ACLF was 10.5-fold ( p < 0.001), 2.6fold ( p < 0.001), and 1.7-fold ( p < 0.001) higher than in HC, CC and ADC. Serum M65-antigen in HBV-ACLF was 31.5-fold ( p < 0.001), 3.3fold ( p < 0.001), and 3.2-fold (p < 0.001) higher than in HC, CC and ADC. Both M30- and M65-antigen significantly correlated with the severity scores of cirrhosis, CTP (both p < 0.001) and MELD (both p < 0.001). ROC analysis revealed that both serum M30-antigen (AUC 0.71, p < 0.001) and M65-antigen (AUC 0.78, p < 0.001) could well discriminate ACLF from ADC. Mixed-ACLF demonstrates the highest level of serum hepatocytes death (M30: 19.6-fold of HC, M65: 85.9-fold of HC) followed by that from Hepatic-ACLF (M30: 9.8-fold of HC, M65: 32.2-fold of HC) and Extrahepatic-ACLF (M30: 5.6-fold of HC, M65: 16.8-fold of HC). Serum M30- and M65-antigen from Extrahepatic-ACLF was relatively low and even close to that from ADC (M30: 6.2-fold of HC, M65: 9.9-fold of HC). Conclusions: Markedly elevated hepatocyte death is crucial for the development of ACLF. Hepatic rather than extra-hepatic precipitating event is the primary reason for massive hepatocyte death. However, extra-hepatic injury may help exaggerating the extent of hepatocyte death in ACLF.
Clinical trials in progress THU-480 MULTICENTRIC PROSPECTIVE STUDY OF VALIDATION OF ANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATED WITH SORAFENIB. INNOVATE STUDY A.C. Gardini1, L. Faloppi2, B. Daniele3, G.F. Foschi4, S. Cascinu5, G. Marisi1, G. Masi6, L. Chessa7, F. Negri8, E. Scarpi1, D. Santini9, J. Corbelli10, N. Silvestris11, E. Tamburini12, V. Zagonel13, M. Scartozzi2. 1 IRST-IRCCS, Forli; 2University of Cagliari, Cagliari; 3Ospedale Rummo, Benevento; 4Interne Medicine, Faenza; 5University of Modena, Modena; 6 University of Pisa, Pisa; 7Dipartimento Scienze Mediche “Mario Aresu”, Cagliari; 8University of Parma, Parma; 9Policlinico Universitario Campus Bio-Medico, Roma; 10Oncology Unit, Faenza; 11Oncologico Bari, Bari; 12 Oncologia Rimini, Rimini; 13IOV Veneto, Padova, Italy E-mail: [email protected] Background and Aims: Preclinical data suggested that significant HCC growth is dependent on angiogenesis, and an increase in tumour dimension may induce vascular endothelial cell proliferation. SNPs in VEGF,VEGFR,HIF1α, angiopoietin2 and eNOS genes have also been correlated to tumour neoangiogenesis through different biological mechanisms. In the ALICE-2 study patients (PT) receiving sorafenib were tested for HIF-1α,VEGF-A and VEGF-C SNPs. At multivariate analysis rs12434438 of HIF-1α,rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors for PFS and OS. At the combined analysis of significant SNPs the presence of 2 favourable alleles of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0.0001) and OS (respectively: 19.0 vs 13.5 vs 7.5 months; p < 0.0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α)select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs(PFS: 2.6 months,p < 0.0001; OS:6.6 months,p < 0.0001). In ePHAS study PT homozygous for a specific haplotype (Ht1:T-4b at eNOS-786/eNOS VNTR) showed a lower median PFS(2.1vs6.2 months, p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)compared to other genotypes. The multivariate analysis confirmed specific haplotype as the only independent prognostic factor.
Journal of Hepatology 2016 vol. 64 | S213–S424
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