- Email: [email protected]
946 HISTOLOGICAL REMISSION IN AUTOIMMUNE HEPATITIS: CAN IT BE PREDICTED?
POSTERS Conclusions: Detection of AMA and ANA-PBC-specific was correlated with disease activity and severity. In particular, the close serological monitoring of anti-sp100 titers by molecular-based ELISA may become an important tool to identify patients with worse outcome and suggest the potential inclusion of those with stable or increase anti-sp100 titers during follow-up in alternative treatment protocols. 945 EPIDEMIOLOGY, NATURAL HISTORY AND OUTCOMES OF PRIMARY BILIARY CIRRHOSIS IN SOUTHERN ISRAEL: A FOLLOW-UP STUDY UP TO 20 YEARS J.-S. Delgado1 , A. Vodonos2 , B. Delgado3 , A. Jotkowitz4 , A. Rosenthal5 , A. Fich5 , V. Novack6 . 1 Gastroenterology & Hepatology, The Barzilai Medical Center, Ben-Gurion University of The Negev, Ashkelon, 2 Clinical Research Center, 3 Pathology, 4 Internal Medicine, 5 Gastroenterology, Soroka Medical Center, Ben-Gurion University, 6 Clinical Research Center, Soroka Medical Center, Ben-Gurion University of The Negev, Beer-Sheva, Israel E-mail: [email protected] Background and Aims: The epidemiology and natural history of primary biliary cirrhosis (PBC) in Israel are unknown. We aimed to determine the epidemiology and outcomes of PBC in Southern Israel from 1990 to 2010. Methods: Thorough case-finding methods and population-based administrative data were used to identify all cases of PBC. We estimated the incidence and prevalence of PBC and evaluated the prognostic factors of unfavorable outcome in our cohort. Results: 138 cases of PBC were identified (94.9% women, Jewish origin (89.1%), median age at diagnosis 55 years). The average annual prevalence of PBC was 255 cases per million. The overall age/sex-adjusted annual incidence of PBC was 10 cases per million (20 per million in women and 2.03 per million in men) from 1990 through 1999 and 20 cases per million (30 per million in women and 0.35 per million in men) from 2000 to 2010. Among 138 incident cases with a total follow-up of 960 personsyears from diagnosis, 30 patients (21.7%) died. Survival in PBC patients was significantly lower than that of the age/sex-matched Israeli population (standardized mortality ratio of 3.9). Mortality was significantly increased in patients with: an initial Model for End-Stage Liver Disease (MELD) score greater than 8 (P < 0.001), with portal hypertension (P < 0.001), with higher bilirubin level (P < 0.001) and in non-responders to ursodeoxycholic acid (UDCA) therapy according to Barcelona criteria (P = 0.005). Out of 138 patients, 95 patients (68.0%) responded to UDCA therapy (Barcelona criteria). None of the responders died during the followup period as opposed to 30 out of 43 (69.8%) of non-responders. In multivariate analysis the factors associated with response to UDCA were: albumin levels above 3.5 g/dL (P < 0.001) and lower degree of fibrosis per liver biopsy (P = 0.003). In non-responders to UDCA, independent predictors of mortality were older age at diagnosis (P = 0.002) and an initial MELD score higher than 8 (P = 0.04). Conclusions: This study addresses the increasing burden of PBC in Israel and confirms the importance of some clinical and therapeutic factors as predictors of long-term prognosis. 946 HISTOLOGICAL REMISSION IN AUTOIMMUNE HEPATITIS: CAN IT BE PREDICTED? H. Dhaliwal1 , B. Hoeroldt2 , A. Dube3 , E. McFarlene1 , M. Karajeh1 , D. Gleeson1 . 1 Liver Unit, Sheffield Teaching Hospitals NHS Trust, Sheffield, 2 Gastroenterology, Rotherham General Hospital, Rotherham, 3 Pathology, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK E-mail: [email protected] Introduction and Aims: A recent report1 suggested that initial treatment of Autoimmune Hepatitis (AIH) with high-dose
prednisolone results in more rapid normalisation of serum ALT and (by implication), improved outcome. However, we have reported2 that persisting histological activity in AIH (Ishak necroinflammatory score (NIS) >3), despite serum ALT normalisation, is associated with fibrosis progression and increased mortality. Here, we aimed to identify, retrospectively, disease or treatment related factors associated with attaining histological remission. Methods: We studied 111 patients with AIH (93 female, median(range) age at diagnosis 57 (14–77) years treated with prednisolone plus azathioprine/mycophenolate, who had attained normalisation of serum ALT and had available follow-up biopsy. Results: Starting daily doses of prednisolone and of azathioprine were 30 (10–60) and 50 (25–150) mg respectively. Time taken to achieve normal serum ALT after starting treatment was 8 (0–144) weeks and showed no correlation with any of: (a) gender, age, serum ALT, or globulin at presentation, (b) NIS or fibrosis grade at diagnostic biopsy, (c) starting dose of prednisolone or azathioprine. Biopsy was repeated 26 (12–90) months after starting treatment. 72 patients (65%) attained histological remission. Comparing these with the 37 patients not in histological remission, there were no significant differences in age, gender, presenting serum ALT, or in NIS or fibrosis stage at diagnostic biopsy. Neither were there differences in either (a) starting or cumulative dose of prednisolone or azathioprine (either absolute or corrected for body weight) or (b) time to achieve normal serum ALT. Only serum globulin at presentation was lower in those who achieved histological remission (42 v 49 g/L, p = 0.01). On multivariate analysis, NIS at follow-up biopsy was independently associated with serum ALT at time of biopsy (p ≤ 0.001) but with none of above baseline, treatment or early response-related variables. Conclusion: We could not identify baseline or treatment-related variables associated with (and thus, potentially predictive of) histological remission. Specifically, we could not establish that histological remission was related to either time to serum ALT normalisation or to starting or cumulative dose of prednisolone. Reference(s) [1] Schramm C et al Hepatology 2010; 52(6): 2247–82. [2] Hoeroldt BS et al. Gut 2009; 58(S1): A18.
947 AZATHIOPRINE METABOLITE CONCENTRATIONS IN AUTOIMMUNE HEPATITIS: RELATIONSHIP TO DISEASE REMISSION H. Dhaliwal1,2 , E. Thornhill2 , R. Anderson2 , E. McFarlane1 , D. Gleeson1 , L. Lennard2 . 1 Liver Unit, Sheffield Teaching Hospitals NHS Trust, 2 Human Metabolism, University of Sheffield, Sheffield, UK E-mail: [email protected] Introduction and Aim: Azathioprine (AZA) is used to maintain remission in AIH but is sometimes ineffective. AZA is a pro-drug and formation of active thioguanine nucleotide (TGN) metabolites varies widely. Competing with TGN formation is drug methylation, catalysed by thiopurine methyltransferase (TPMT). The methylated drug is inactive, but the methyl-mercaptopurine nucleotide metabolites (MeMPs) may not be. Previous studies, based mainly on single measurements, have not shown a relationship between TGN levels and clinical efficacy. We assessed the relationship between mean of several metabolite levels (TGNs and MeMPs), and therapeutic response in AIH patients prescribed a constant dose of AZA for remission maintenance. Methods: Erythrocyte TGNs and MeMPs were measured on serial blood samples by established techniques over two years. Average TGNs (avTGNs) and MeMPs (avMeMPs) concentrations for each patient at a constant AZA dose were analysed. Therapeutic response was defined as maintenance of remission on a given dose of AZA. Relapse was defined by the IAIHG criteria (ALT >2×ULN or symptoms+ALT >ULN).
Journal of Hepatology 2012 vol. 56 | S225–S388
S369
prednisolone results in more rapid normalisation of serum ALT and (by implication), improved outcome. However, we have reported2 that persisting histological activity in AIH (Ishak necroinflammatory score (NIS) >3), despite serum ALT normalisation, is associated with fibrosis progression and increased mortality. Here, we aimed to identify, retrospectively, disease or treatment related factors associated with attaining histological remission. Methods: We studied 111 patients with AIH (93 female, median(range) age at diagnosis 57 (14–77) years treated with prednisolone plus azathioprine/mycophenolate, who had attained normalisation of serum ALT and had available follow-up biopsy. Results: Starting daily doses of prednisolone and of azathioprine were 30 (10–60) and 50 (25–150) mg respectively. Time taken to achieve normal serum ALT after starting treatment was 8 (0–144) weeks and showed no correlation with any of: (a) gender, age, serum ALT, or globulin at presentation, (b) NIS or fibrosis grade at diagnostic biopsy, (c) starting dose of prednisolone or azathioprine. Biopsy was repeated 26 (12–90) months after starting treatment. 72 patients (65%) attained histological remission. Comparing these with the 37 patients not in histological remission, there were no significant differences in age, gender, presenting serum ALT, or in NIS or fibrosis stage at diagnostic biopsy. Neither were there differences in either (a) starting or cumulative dose of prednisolone or azathioprine (either absolute or corrected for body weight) or (b) time to achieve normal serum ALT. Only serum globulin at presentation was lower in those who achieved histological remission (42 v 49 g/L, p = 0.01). On multivariate analysis, NIS at follow-up biopsy was independently associated with serum ALT at time of biopsy (p ≤ 0.001) but with none of above baseline, treatment or early response-related variables. Conclusion: We could not identify baseline or treatment-related variables associated with (and thus, potentially predictive of) histological remission. Specifically, we could not establish that histological remission was related to either time to serum ALT normalisation or to starting or cumulative dose of prednisolone. Reference(s) [1] Schramm C et al Hepatology 2010; 52(6): 2247–82. [2] Hoeroldt BS et al. Gut 2009; 58(S1): A18.
947 AZATHIOPRINE METABOLITE CONCENTRATIONS IN AUTOIMMUNE HEPATITIS: RELATIONSHIP TO DISEASE REMISSION H. Dhaliwal1,2 , E. Thornhill2 , R. Anderson2 , E. McFarlane1 , D. Gleeson1 , L. Lennard2 . 1 Liver Unit, Sheffield Teaching Hospitals NHS Trust, 2 Human Metabolism, University of Sheffield, Sheffield, UK E-mail: [email protected] Introduction and Aim: Azathioprine (AZA) is used to maintain remission in AIH but is sometimes ineffective. AZA is a pro-drug and formation of active thioguanine nucleotide (TGN) metabolites varies widely. Competing with TGN formation is drug methylation, catalysed by thiopurine methyltransferase (TPMT). The methylated drug is inactive, but the methyl-mercaptopurine nucleotide metabolites (MeMPs) may not be. Previous studies, based mainly on single measurements, have not shown a relationship between TGN levels and clinical efficacy. We assessed the relationship between mean of several metabolite levels (TGNs and MeMPs), and therapeutic response in AIH patients prescribed a constant dose of AZA for remission maintenance. Methods: Erythrocyte TGNs and MeMPs were measured on serial blood samples by established techniques over two years. Average TGNs (avTGNs) and MeMPs (avMeMPs) concentrations for each patient at a constant AZA dose were analysed. Therapeutic response was defined as maintenance of remission on a given dose of AZA. Relapse was defined by the IAIHG criteria (ALT >2×ULN or symptoms+ALT >ULN).
Journal of Hepatology 2012 vol. 56 | S225–S388
S369