- Email: [email protected]
543 INTERLEUKIN 17F CONCENTRATION IS ASSOCIATED WITH DEGREE OF LIVER DAMAGE IN ALCOHOLIC LIVER DISEASE
POSTERS Only plasma from AAH patients showed elevated levels of proinflammatory IL-6/IL-8 (p = 0.03/0.02) and Galectin-9 (p = 0.04), a known negative regulator of the T-cell immune response. Conclusions: Patients with AAH have impaired anti-bacterial innate and adaptive immunity, which is characterised by the hyperexpression of immune-inhibitory receptors on neutrophils and T-cells. We propose that PD-1/PD-L1 and TIM-3/Galectin-9 signatures not only represent markers of infection susceptibility in patients with AAH but therapeutic targets whereby blockade of these pathways could allow reconstitution of effective host immunity. 542 NEW ALGORITHM TO ASSESS FIBROSIS STAGE IN ALCOHOLIC LIVER DISEASE BY TRANSIENT ELASTOGRAPHY C. Dietrich1 , J.B. Trabut2 , H.K. Seitz1 , S. Pol2 , S. Mueller1 . 1 Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany; 2 Service d’H´epatologie, Hˆ opital Cochin, APHP, Paris, France E-mail: [email protected] Aim: Liver stiffness (LS) is the novel gold standard to assess fibrosis stage in patients with alcoholic liver disease (ALD). However, we could recently demonstrate that alcoholic steatohepatitis needs to be considered (transaminase levels) prior to fibrosis assessment since it increases LS independently of fibrosis stage. We here validate our novel algorithm in a larger two-center study population of heavy trinkers undergoing alcohol detoxification. Methods: 417 patients admitted for alcohol detoxification were included both from France (n = 137) and Germany (n = 280) undergoing sequential LS measurement by transient elastography and lab tests at day of admission and release. 251 patients had valid LS measurements (IQR <30%, success rate>60%) for both time points. Results: Overally, LS decreased in 10% with a mean decrease of LS by 1.9 kPa (7.2%) over the mean observation interval of 6.4 days. The decrease of LS translated into a lower fibrosis stage in 24.7%. In some cases, the degree of fibrosis decreased by three stages. The decrease of LS was significantly correlated with GOT levels (r = 0.235, p < 0.05) but no other liver parameters. Receiver operating curve analysis indicated that a cut-off value of 104 U/L GOT has the highest sensitivity and specificity in predicting a decrease of LS during alcohol detoxification. Comparison between patients with initially high GOT>100 U/l and normal transaminases indicated that elevated GOT is responsible for the drop of LS-based fibrosis in 20%. In contrast, only a minority of 2% had increased LS-based fibrosis stage. Conclusion: This larger two-center trial confirms previous findings that coexisting steatohepatitis of GOT>100 U/L markedly increases LS in patients with ALD independent of fibrosis stage. Ca. 20% of patients with elevated GOT levels eventually have a lower LS-based fibrosis stage. Therefore, normalization of GOT levels is required to correctly interpret liver stiffness in patients with ALD. 543 INTERLEUKIN 17F CONCENTRATION IS ASSOCIATED WITH DEGREE OF LIVER DAMAGE IN ALCOHOLIC LIVER DISEASE A. Parfieniuk-Kowerda, T. Szulzyk, M. Swiderska, T.W. Lapinski, J. Jaroszewicz, R. Flisiak. Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland E-mail: anna.parfi[email protected] Background and Aims: The Th17 lymphocytes, subset of T helper CD4+ lymphocytes, play a role in pathogenesis of inflammatory and autoimmune diseases. Recent reports have proven the influence of Th17 lymphocytes on inflammatory and autoimmune reactions in alcoholic liver disease (ALD). Activated Th17 T-cells, infiltrating liver tissue, recruit neutrophils thus enhancing inflammatory response S222
in ALD. Our study aims to assess serum interleukin 17F (IL-17F) and interleukin 17A (IL-17A) concentration in ALD with regards to the advancement of liver damage. Methods: Serum concentrations of IL-17F and IL-17A were assessed by ELISA method in 88 patients with ALD. The results were analysed with regard to the degree of hepatic damage clasified according to MELD (Model of End-Stage Liver Disease), Child–Pugh score and GAHS (Glasgow Alcoholic Hepatitis Score). Control group included 30 healthy volunteers. Results: Serum concentration of IL-17F was significantly elevated in ALD compared to control group (median: 15.46 pg/mL vs. 8.17 pg/mL, p = 0.006). There were significant positive correlations between serum IL-17F concentration and serum bilirubin (Rs=0.23, p = 0.03), INR (Rs=0.29, p = 0.005) and degree of liver damage in MELD (Rs=0.23, p = 0.03), but not in Child–Pugh and GAHS classification. Serum IL-17A concentrations were comparable in ALD and control groups. In ALD group serum IL-17A positively correlated with serum IL-17F (RS =0.26, p = 0.01) and INR (RS =0.22, p = 0.03). Conclusions: Serum IL-17F, but not IL-17A, is increased in ALD. Il-17F correlates with the progression of liver damage in ALD demonstrated through MELD classification. 544 THE DISCOVERY OF BETTER BIOMARKERS OF DRUG INDUCED LIVER INJURY (DILI) NEEDS TO USE OTHER ENDPOINTS THAN ALT. A PILOT PROOF OF CONCEPT STUDY H. Perazzo1 , M. Merz2 , T. Poynard1 , SAFE-T Consortium WP3. 1 APHP UPMC Paris Liver Center, Paris, France; 2 Novartis, Bonn, Germany E-mail: [email protected] Background: Severe acute DILI are identified and classified using increase of ALT. The most popular criteria are Temple’s corollary (3×ULN-ALT) and Hy’s law criteria (3×ULN-ALT and bilirubin>2×ULN (34 mmol/L). To assess the performance of better DILI biomarkers than ALT, it is mandatory to use another endpoints than ALT, without too low prevalence. The aim was to check the utility of biological and clinical endpoints ‘ALT-free’ in a prospective pilot study before starting a validation study. Methods: During and episode of DILI biochemical severity (B-sDILI) was define as an increase of total bilirubin as up to 2xN (34 micromol/L) if <2xN at baseline; or an increase of 10 micromol/L if baseline>2xN; clinical severity (C-sDILI) was define as DILI-related death, transplantation or hospitalization. As a proof of concept we compare the predictive performance of serum apolipoprotein-A1 (ApoA1) and ActiTest (AT) as candidate DILI-biomarker versus ALT, the Standard of Care. As part of a pilot prospective study of the SAFE-T consortium we assess consecutive patients hospitalized in a tertiary referral center for DILI, using a centralized lab and an independent adjudication committee. Results: In one year 25 patients were included, 8 females, mean 48 years of age, 8 acetaminophen alone or in combination. Seven cases (28%) of C-sDILI occurred: 1 death, 1 transplantation and specific hospitalization in other 5 cases; B-sDILI occurred in 6 (24%); 12 (44%) cases had neither C or B-sDILI. The repeated 3 biomarkers had significant kinetics (repeated variance analysis P < 0.01) during 12-weeks follow-up [mean 6 samples/patient], with significant predictive values at baseline for CB-sDILI: AUROCs for AT/APOA1/ALT were 0.74 (95% CI 0.45–0.89; P = 0.01), 0.69 (0.35–0.87; P = 0.07), and 0.71 (0.42–0.87; P = 0.03), without differences between AT/ApoA1 and ALT (P = 0.88/P = 0.18). At 12 Weeks only 6 cases had totally normal liver function tests as well as normal fibrosis biomarkers (FibroTest/Fibroscan). Three cases with repeated cycles of chemotherapy had adaptive profiles, which deserve a specific analysis. Gilbert syndrome, atazanavir co-prescription, hemolysis, and cardiac insufficiency were factors associated with total bilirubin or GGT variability.
Journal of Hepatology 2013 vol. 58 | S63–S227
in ALD. Our study aims to assess serum interleukin 17F (IL-17F) and interleukin 17A (IL-17A) concentration in ALD with regards to the advancement of liver damage. Methods: Serum concentrations of IL-17F and IL-17A were assessed by ELISA method in 88 patients with ALD. The results were analysed with regard to the degree of hepatic damage clasified according to MELD (Model of End-Stage Liver Disease), Child–Pugh score and GAHS (Glasgow Alcoholic Hepatitis Score). Control group included 30 healthy volunteers. Results: Serum concentration of IL-17F was significantly elevated in ALD compared to control group (median: 15.46 pg/mL vs. 8.17 pg/mL, p = 0.006). There were significant positive correlations between serum IL-17F concentration and serum bilirubin (Rs=0.23, p = 0.03), INR (Rs=0.29, p = 0.005) and degree of liver damage in MELD (Rs=0.23, p = 0.03), but not in Child–Pugh and GAHS classification. Serum IL-17A concentrations were comparable in ALD and control groups. In ALD group serum IL-17A positively correlated with serum IL-17F (RS =0.26, p = 0.01) and INR (RS =0.22, p = 0.03). Conclusions: Serum IL-17F, but not IL-17A, is increased in ALD. Il-17F correlates with the progression of liver damage in ALD demonstrated through MELD classification. 544 THE DISCOVERY OF BETTER BIOMARKERS OF DRUG INDUCED LIVER INJURY (DILI) NEEDS TO USE OTHER ENDPOINTS THAN ALT. A PILOT PROOF OF CONCEPT STUDY H. Perazzo1 , M. Merz2 , T. Poynard1 , SAFE-T Consortium WP3. 1 APHP UPMC Paris Liver Center, Paris, France; 2 Novartis, Bonn, Germany E-mail: [email protected] Background: Severe acute DILI are identified and classified using increase of ALT. The most popular criteria are Temple’s corollary (3×ULN-ALT) and Hy’s law criteria (3×ULN-ALT and bilirubin>2×ULN (34 mmol/L). To assess the performance of better DILI biomarkers than ALT, it is mandatory to use another endpoints than ALT, without too low prevalence. The aim was to check the utility of biological and clinical endpoints ‘ALT-free’ in a prospective pilot study before starting a validation study. Methods: During and episode of DILI biochemical severity (B-sDILI) was define as an increase of total bilirubin as up to 2xN (34 micromol/L) if <2xN at baseline; or an increase of 10 micromol/L if baseline>2xN; clinical severity (C-sDILI) was define as DILI-related death, transplantation or hospitalization. As a proof of concept we compare the predictive performance of serum apolipoprotein-A1 (ApoA1) and ActiTest (AT) as candidate DILI-biomarker versus ALT, the Standard of Care. As part of a pilot prospective study of the SAFE-T consortium we assess consecutive patients hospitalized in a tertiary referral center for DILI, using a centralized lab and an independent adjudication committee. Results: In one year 25 patients were included, 8 females, mean 48 years of age, 8 acetaminophen alone or in combination. Seven cases (28%) of C-sDILI occurred: 1 death, 1 transplantation and specific hospitalization in other 5 cases; B-sDILI occurred in 6 (24%); 12 (44%) cases had neither C or B-sDILI. The repeated 3 biomarkers had significant kinetics (repeated variance analysis P < 0.01) during 12-weeks follow-up [mean 6 samples/patient], with significant predictive values at baseline for CB-sDILI: AUROCs for AT/APOA1/ALT were 0.74 (95% CI 0.45–0.89; P = 0.01), 0.69 (0.35–0.87; P = 0.07), and 0.71 (0.42–0.87; P = 0.03), without differences between AT/ApoA1 and ALT (P = 0.88/P = 0.18). At 12 Weeks only 6 cases had totally normal liver function tests as well as normal fibrosis biomarkers (FibroTest/Fibroscan). Three cases with repeated cycles of chemotherapy had adaptive profiles, which deserve a specific analysis. Gilbert syndrome, atazanavir co-prescription, hemolysis, and cardiac insufficiency were factors associated with total bilirubin or GGT variability.
Journal of Hepatology 2013 vol. 58 | S63–S227