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1362 CLINICAL BUT NOT HISTOLOGICAL FACTORS PREDICT LONG-TERM PROGNOSIS IN PATIENTS WITH BIOPSY PROVEN ADVANCED ALCOHOLIC LIVER DISEASE
POSTERS Conclusion: in this cohort, overall mortality rate of 3rd (M3) to 6th month (M6) follow-up was 32.9%, this one reaching 80% for Lille score above 0.45. In multivariate analysis, predictive factors of late death at 6 months are the absence of alcohol withdrawal in M1 (p = 0.01), the existence of a documented infection at M1 (p = 0.04) and the MELD-Na score >27 at M1 (p = 0.004). From M3 follow-up, the causes of death are no longer related to the initial severity of the ADT. 1361 ALCOHOL-INDUCED LIVER TOXICITY IS ASSOCIATED WITH NEUTROPHIL DYSFUNCTION IN A NOVEL IN-VITRO MODEL OF ACUTE LIVER INJURY L.J. Markwick1,2 , E. Palma1 , A. Riva1 , R. Williams1 , D. Clemens3,4 , D. Shawcross2 , S. Chokshi1 . 1 Institute of Hepatology, Foundation for Liver Research, 2 Institute of Liver Studies, King’s College London at King’s College Hospital, London, UK; 3 University of Nebraska Medical Center, 4 Veteran Affairs Medical Center, Omaha, NE, USA E-mail: [email protected] Background and Aims: Sepsis is a major cause of mortality in patients with alcohol-induced acute and chronic liver failure (ALF/CLF). Neutrophils are a major innate immune cell subset involved in the first line of defence against infection and circulating neutrophil dysfunction has been reported in patients with ALF/CLF. However, there is a paucity of understanding regarding the mechanisms involved in this dysfunction. In this study we aimed to characterise the precise relationship between neutrophil dysfunction and alcohol-induced liver damage with a novel in vitro model mimicking the in vivo interactions of neutrophils and hepatocytes. Methods: We cultured a well-characterised neutrophil-line HL60 either directly with ethanol or with supernatants taken from ethanol metabolising-human hepatoma cell lines VL-17A (positive for alcohol-dehydrogenase and CYP2E1) cultured in the presence of safe levels (10mM) and toxic levels (250mM) of ethanol reflecting real-life human alcohol consumption for 24 hours. Neutrophil function was evaluated by TLR expression, chemotaxis, phagocytosis and respiratory burst assays. Cell supernatants were also collected for cytokine profiling and to quantitate levels of ammonia and ethanol metabolites. The effect of ethanol on the functional activities of neutrophils isolated from both normal and ALF/CLF patients will also be assessed. Results: Supernatants collected from the hepatoma line VL17A cultured with 250mM ethanol (representative of an alcohol binge) significantly reduced the phagocytic capacity of the HL60-neutrophil line (p < 0.05). This was greater than the effect of the same concentration of ethanol applied directly to the neutrophils (p < 0.05). Our preliminary data also suggests that the metabolised ethanol inhibits chemotaxis of the HL60-neutrophil cells towards a gradient of fMLP. Furthermore, we observed a reduction of TLR4 expression. Conclusions: We describe a novel model for investigating the correlates of dysfunctional innate immunity during acute alcoholinduced liver injury. We identify that alcohol does impair neutrophil function directly but this is profoundly increased after hepatocyte alcohol metabolism implicating a causal link between liver injury and impairment of antibacterial neutrophil functions.
1362 CLINICAL BUT NOT HISTOLOGICAL FACTORS PREDICT LONG-TERM PROGNOSIS IN PATIENTS WITH BIOPSY PROVEN ADVANCED ALCOHOLIC LIVER DISEASE S. Masson1,2 , I. Emmerson1 , E. Henderson1 , E. Fletcher1 , A.D. Burt2 , C.P. Day2 , S.F. Stewart3 . 1 Liver Transplant Unit, Freeman Hospital, 2 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 3 Mater Misericordiae University Hospital, Dublin, Ireland E-mail: [email protected] Introduction/aim: Alcoholic liver disease (ALD) is a threat to the health of the European population. It remains a common indications for liver transplantation and a leading cause of death. Despite this, the long term clinical course and predictive factors of survival in advanced ALD have not been well described. We aimed to identify factors that predict 15 year survival in out-patients with biopsyproven ALD. Methods: Patients (n = 134) with biopsy-proven advanced (stage III OR IV) ALD were followed-up for fifteen years or until death or transplantation. At baseline, clinical and laboratory data were collected. On biopsy, the presence of cirrhosis and histological features (fat severity, lymphocyte and neutrophil infiltration) were scored semi-quantitatively. Results: Median age was 51 (29–67) and the majority (72%) were male. All had history of alcohol excess (>80 g/day [M], 50 g/d [F]). Patients were followed until death (n = 99; median 62m), OLT (n = 5; median 96m) or are still alive (n = 33; median 187m). Overall, the 5, 10 and 15-year survival was 64, 40 and 26%, respectively. Baseline characteristics are shown according to outcome (Table 1). In multivariate analysis age (p = 0.01), smoking (p = 0.01), persistent drinking (p < 0.01) and serum albumin at baseline (p = 0.02) were associated with significantly increased risk of death. No histological features correlated with prognosis. Table: Characteristics according to 15 year survival Characteristic
Alive (n = 32)
Dead (n = 104)
OR (95% CI)
p value
Age Smoker Subsequent abstinence Ascites
48 (44–54) IQR 12 (50%) 13 (42%) 2 (7%)
53 (47–58) IQR 72 (73%) 17 (17%) 20 (21%)
<0.01 0.04 <0.01 0.11
Platelet count Serum Albumin Child-Pugh MELD UKELD
171 (146–214) 44 (42–47) 9 (9–10) 7 (6–9) 47 (47–50)
125 (89–191) 39 (32–44) 10 (9–12) 11 (8–15) 51 (49–55)
1.08 (1.02–1.13) 2.53 (1.10–5.83) 0.28 (0.12–0.69) 3.42 (0.75– 15.64) 1.00 (0.99–1.00) 0.83 (0.75–0.92) 1.76 (1.19–2.59) 1.18 (1.06–1.32) 1.25 (1.09–1.45)
0.25 <0.01 <0.01 <0.01 <0.01
Conclusion: In out-patients with biopsy-proven advanced ALD, clinical but not histological factors determine prognosis. Age, persistent alcohol intake, smoking habit and serum albumin are independent poor prognostic factors. Abstinence from alcohol and smoking cessation should be the priorities in the long-term management of ALD. 1363 METABOLIC PROFILES ASSOCIATED WITH THE SEVERITY OF ALCOHOLIC HEPATITIS AND THE RESPONSE TO TREATMENT. PRELIMINARY RESULTS J. Michelena1 , C. Alonso2 , J. Barr2 , J. Altamirano1 , I. Martinez Arranz2 , R. Bataller1 , M.L. Martinez Chantar3 , A. Castro2 , J.M. Mato3 , J. Caballeria1 . 1 Liver Unit, Hospital Cl´ınic, IDIBAPS, CIBERehd, Barcelona, 2 OWLGenomics, 3 CICbioGUNE, CIBERehd, Derio, Spain E-mail: [email protected] Background and Aims: Alcoholic hepatitis (AH) includes a spectrum of diseases that range from mild injury to severe, life threatening injury. Corticosteroids are the only recommended therapy for severe AH. However, a percentage of patients fail to respond to corticosteroid treatment and, on the other hand, complications, especially infections, occur in almost 25% of patients during corticosteroid treatment. The aim of this ongoing study was
Journal of Hepatology 2012 vol. 56 | S389–S548
S535
1362 CLINICAL BUT NOT HISTOLOGICAL FACTORS PREDICT LONG-TERM PROGNOSIS IN PATIENTS WITH BIOPSY PROVEN ADVANCED ALCOHOLIC LIVER DISEASE S. Masson1,2 , I. Emmerson1 , E. Henderson1 , E. Fletcher1 , A.D. Burt2 , C.P. Day2 , S.F. Stewart3 . 1 Liver Transplant Unit, Freeman Hospital, 2 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 3 Mater Misericordiae University Hospital, Dublin, Ireland E-mail: [email protected] Introduction/aim: Alcoholic liver disease (ALD) is a threat to the health of the European population. It remains a common indications for liver transplantation and a leading cause of death. Despite this, the long term clinical course and predictive factors of survival in advanced ALD have not been well described. We aimed to identify factors that predict 15 year survival in out-patients with biopsyproven ALD. Methods: Patients (n = 134) with biopsy-proven advanced (stage III OR IV) ALD were followed-up for fifteen years or until death or transplantation. At baseline, clinical and laboratory data were collected. On biopsy, the presence of cirrhosis and histological features (fat severity, lymphocyte and neutrophil infiltration) were scored semi-quantitatively. Results: Median age was 51 (29–67) and the majority (72%) were male. All had history of alcohol excess (>80 g/day [M], 50 g/d [F]). Patients were followed until death (n = 99; median 62m), OLT (n = 5; median 96m) or are still alive (n = 33; median 187m). Overall, the 5, 10 and 15-year survival was 64, 40 and 26%, respectively. Baseline characteristics are shown according to outcome (Table 1). In multivariate analysis age (p = 0.01), smoking (p = 0.01), persistent drinking (p < 0.01) and serum albumin at baseline (p = 0.02) were associated with significantly increased risk of death. No histological features correlated with prognosis. Table: Characteristics according to 15 year survival Characteristic
Alive (n = 32)
Dead (n = 104)
OR (95% CI)
p value
Age Smoker Subsequent abstinence Ascites
48 (44–54) IQR 12 (50%) 13 (42%) 2 (7%)
53 (47–58) IQR 72 (73%) 17 (17%) 20 (21%)
<0.01 0.04 <0.01 0.11
Platelet count Serum Albumin Child-Pugh MELD UKELD
171 (146–214) 44 (42–47) 9 (9–10) 7 (6–9) 47 (47–50)
125 (89–191) 39 (32–44) 10 (9–12) 11 (8–15) 51 (49–55)
1.08 (1.02–1.13) 2.53 (1.10–5.83) 0.28 (0.12–0.69) 3.42 (0.75– 15.64) 1.00 (0.99–1.00) 0.83 (0.75–0.92) 1.76 (1.19–2.59) 1.18 (1.06–1.32) 1.25 (1.09–1.45)
0.25 <0.01 <0.01 <0.01 <0.01
Conclusion: In out-patients with biopsy-proven advanced ALD, clinical but not histological factors determine prognosis. Age, persistent alcohol intake, smoking habit and serum albumin are independent poor prognostic factors. Abstinence from alcohol and smoking cessation should be the priorities in the long-term management of ALD. 1363 METABOLIC PROFILES ASSOCIATED WITH THE SEVERITY OF ALCOHOLIC HEPATITIS AND THE RESPONSE TO TREATMENT. PRELIMINARY RESULTS J. Michelena1 , C. Alonso2 , J. Barr2 , J. Altamirano1 , I. Martinez Arranz2 , R. Bataller1 , M.L. Martinez Chantar3 , A. Castro2 , J.M. Mato3 , J. Caballeria1 . 1 Liver Unit, Hospital Cl´ınic, IDIBAPS, CIBERehd, Barcelona, 2 OWLGenomics, 3 CICbioGUNE, CIBERehd, Derio, Spain E-mail: [email protected] Background and Aims: Alcoholic hepatitis (AH) includes a spectrum of diseases that range from mild injury to severe, life threatening injury. Corticosteroids are the only recommended therapy for severe AH. However, a percentage of patients fail to respond to corticosteroid treatment and, on the other hand, complications, especially infections, occur in almost 25% of patients during corticosteroid treatment. The aim of this ongoing study was
Journal of Hepatology 2012 vol. 56 | S389–S548
S535