- Email: [email protected]
P352 THE NATURAL HISTORY OF AUTOIMMUNE HEPATITIS (AIH) PRESENTING WITH JAUNDICE
POSTERS to the advanced disease (stage III-IV: OR 78, 95% CI 5.55–1108.61, p < 0.05). The risk of miscarriage was inversely associated with the histological stage (I-II: OR 0.32, 95% CI 0.10–0.97, p < 0.05). Eight pregnancies occurred after the diagnosis of PBC in 6 patients (two of them with stage IV). All pregnancies had a favorable course; UDCA was continued and no worsening of the disease was observed. Conclusions: Successful completion of pregnancy is a realistic expectation for PBC patients; monitoring of pregnancy and delivery, however, is required due a potential risk of child birth complications. P351 TNFa CLEAVING ENZYME (TACE/ADAM 17) IS AN IMPORTANT DRIVER OF CHOLESTASIS-ASSOCIATED LIVER INJURY AND SICKNESS BEHAVIOR DEVELOPMENT H.H. Nguyen1,2 , C. D’Mello2 , S.J. Urbanski3 , T.S. Le2 , T. Le2 , M.G. Swain2,4 . 1 Internal Medicine, 2 Snyder Institute for Chronic Diseases, 3 Department of Pathology & Laboratory Medicine, 4 Department of Gastroenterology/Hepatology, University of Calgary, Calgary, AB, Canada E-mail: [email protected] Background and Aims: TNFa has been linked to liver injury and symptoms (sickness behavior in animals) associated with cholestatic liver diseases, including PSC and PBC. Unfortunately, current medical therapy is limited for PBC, and is non-existent for PSC. TACE (ADAM17) is an enzyme critical for the release of soluble TNFa. Therefore, the aim of our study was to delineate the role of TACE in the development of cholestasis-associated liver injury and sickness behavior. Methods: The mouse (C57BL/6) bile duct ligation (BDL) model of cholestasis was utilized, and hepatic TACE expression determined 10 days post-surgery. The impact of TACE inhibition (using the compound DPC 333) on liver injury (serum liver biochemistry and histology), and cholestasis-associated sickness behavior development, were examined. In addition, hepatic TACE expression was also assessed in human cholestatic liver diseases (PBC, PSC) and normal controls.
Figure: Immunohistochemical staining for TACE expression in representative (n = 3 for each group) liver biopsy specimens from normal liver, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) patients. TACE protein expression (red staining) is strikingly increased in PBC and PSC liver samples compared to normal liver, and is localized to hepatocytes (small black arrows), cholangiocytes (large black arrows), and inflammatory cells found mainly in the portal areas of PBC and PSC liver samples (white filled arrows). Pictures were taken at 20×.
Results: Hepatic TACE expression was increased in BDL mice vs sham controls. Moreover, a similar increase in TACE expression was found in livers from PSC and PBC patients’ vs normal control livers. TACE inhibition in BDL mice by DPC 333 resulted in a S184
significant improvement in BDL-associated liver injury (biochemical and histology) as well as a marked improvement in sickness behavior development. Conclusions: We document for the first time increased hepatic TACE expression in cholestatic mice, and in cholestatic patients with PBC and PSC. In addition, TACE inhibition improved cholestasis-related liver damage and associated sickness behaviors in cholestatic mice. Therefore, TACE may represent a novel target for the treatment of cholestatic liver diseases. P352 THE NATURAL HISTORY OF AUTOIMMUNE HEPATITIS (AIH) PRESENTING WITH JAUNDICE O.J. Froud1 , V. Panayi1 , L. Vine1 , P. Laurent1 , K. Woolson1 , J.G. Hunter1 , R.G. Madden1 , C. Miller1 , B. Stableforth1 , I.A. Murray1 , J. Palmer2 , N. Harris3 , J. Mathew3 , H.R. Dalton1,4 . 1 Cornwall Gastrointestinal Unit, 2 Research and Development, 3 Histopathology, Royal Cornwall Hospital, 4 European Centre for Environment and Human Health, University of Exeter Medical School, Truro, United Kingdom E-mail: [email protected] Background and Aims: 40% of patients with AIH present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis. The aims of this study were to describe the natural history of AIH in patients presenting with jaundice/hepatitis and determine if the diagnosis could have been made at an earlier stage prior to presentation. Methods: Retrospective review of 2148 consecutive patients presenting with jaundice to the jaundice hotline clinic, Truro, Cornwall, UK, over a 15 year period (1998–2013), with review laboratory data over a 23 year period (1990–2013). Results: 47/2148 (2%) had criterion-referenced AIH, 35F:12M, median age 65 years (range 15–91). Median (range) bilirubin 139 mmol/L (23–634), ALT 687 IU/L (22–2519). 23/46 (50%) patients were cirrhotic on biopsy. 11/47 (23%) died: median diagnosis to death 5 months (range 1–59), median age 72 (range 59–91). 8/11 patients died of liver-related causes, all were cirrhotic. Weight loss (p = 0.04), presence of cirrhosis (p = 0.003) and varices (p = 0.002) were more common in those who died. 6/8 (75%) liver deaths were <6 months following diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (p = 0.011, p = 0.002). 33/47 (70%) had LFT results prior to presentation. Of these, 16 (49%) had previous abnormal ALT results and 8 (62%) of these were cirrhotic at presentation.
Figure: ALT results at presentation with historical trends.
Conclusions: AIH presenting with jaundice/hepatitis occurs in older females, 50% are cirrhotic, and liver-related mortality is high. Some of these deaths were potentially preventable by earlier diagnosis, as they had previously abnormal LFTs which had not been investigated.
Journal of Hepatology 2014 vol. 60 | S67–S214
Figure: Immunohistochemical staining for TACE expression in representative (n = 3 for each group) liver biopsy specimens from normal liver, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) patients. TACE protein expression (red staining) is strikingly increased in PBC and PSC liver samples compared to normal liver, and is localized to hepatocytes (small black arrows), cholangiocytes (large black arrows), and inflammatory cells found mainly in the portal areas of PBC and PSC liver samples (white filled arrows). Pictures were taken at 20×.
Results: Hepatic TACE expression was increased in BDL mice vs sham controls. Moreover, a similar increase in TACE expression was found in livers from PSC and PBC patients’ vs normal control livers. TACE inhibition in BDL mice by DPC 333 resulted in a S184
significant improvement in BDL-associated liver injury (biochemical and histology) as well as a marked improvement in sickness behavior development. Conclusions: We document for the first time increased hepatic TACE expression in cholestatic mice, and in cholestatic patients with PBC and PSC. In addition, TACE inhibition improved cholestasis-related liver damage and associated sickness behaviors in cholestatic mice. Therefore, TACE may represent a novel target for the treatment of cholestatic liver diseases. P352 THE NATURAL HISTORY OF AUTOIMMUNE HEPATITIS (AIH) PRESENTING WITH JAUNDICE O.J. Froud1 , V. Panayi1 , L. Vine1 , P. Laurent1 , K. Woolson1 , J.G. Hunter1 , R.G. Madden1 , C. Miller1 , B. Stableforth1 , I.A. Murray1 , J. Palmer2 , N. Harris3 , J. Mathew3 , H.R. Dalton1,4 . 1 Cornwall Gastrointestinal Unit, 2 Research and Development, 3 Histopathology, Royal Cornwall Hospital, 4 European Centre for Environment and Human Health, University of Exeter Medical School, Truro, United Kingdom E-mail: [email protected] Background and Aims: 40% of patients with AIH present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis. The aims of this study were to describe the natural history of AIH in patients presenting with jaundice/hepatitis and determine if the diagnosis could have been made at an earlier stage prior to presentation. Methods: Retrospective review of 2148 consecutive patients presenting with jaundice to the jaundice hotline clinic, Truro, Cornwall, UK, over a 15 year period (1998–2013), with review laboratory data over a 23 year period (1990–2013). Results: 47/2148 (2%) had criterion-referenced AIH, 35F:12M, median age 65 years (range 15–91). Median (range) bilirubin 139 mmol/L (23–634), ALT 687 IU/L (22–2519). 23/46 (50%) patients were cirrhotic on biopsy. 11/47 (23%) died: median diagnosis to death 5 months (range 1–59), median age 72 (range 59–91). 8/11 patients died of liver-related causes, all were cirrhotic. Weight loss (p = 0.04), presence of cirrhosis (p = 0.003) and varices (p = 0.002) were more common in those who died. 6/8 (75%) liver deaths were <6 months following diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (p = 0.011, p = 0.002). 33/47 (70%) had LFT results prior to presentation. Of these, 16 (49%) had previous abnormal ALT results and 8 (62%) of these were cirrhotic at presentation.
Figure: ALT results at presentation with historical trends.
Conclusions: AIH presenting with jaundice/hepatitis occurs in older females, 50% are cirrhotic, and liver-related mortality is high. Some of these deaths were potentially preventable by earlier diagnosis, as they had previously abnormal LFTs which had not been investigated.
Journal of Hepatology 2014 vol. 60 | S67–S214