Gut-Liver Axis in Cystic Fibrosis: Lack of Association between Intestinal Inflammation and Liver Disease in Adult Cystic Fibrosis Patients after Lung Transplantation

POSTER PRESENTATIONS SAT-377 RESCUE WITH STEROIDS IN PATIENTS WITH AUTOIMMUNE ACUTE JAUNDICED HEPATITIS V. Cervera1, M.E. Serio1, V. Descalzi1, S. Raffa1. 1Hepatology Unit, Fundacion Favaloro, Buenos Aires, Argentina E-mail: [email protected] Background and Aims: Autoimmune hepatitis (AIH) has a wide spectrum of clinical manifestations, being jaundice a significant marker of severity. The decision to start steroids treatment in this population is difficult in clinical practice. Aims: to evaluate the degree of response, clinical predictors of outcome and survival in acute jaundiced AIH. Methods: Thirty three consecutive patientes ( pts) with acute jaundiced AIH seen at our center in the last 5 years were included in the study. Inclusion criteria were: bilirrubin >2.5 mg/dL, naïve to treatment, older than 15 years old and AIH diagnosis according to the international group score. In those pts treated with steroid, response was defined as complete, partial or treatment failure in concurrence to 2010 AASLD Guideline. Clinical, biochemical and histological variables associated with treatment failure were analyzed by nonparametric tests (Chi square and U Mann-Whitney). Overall survival and free liver transplant (LT) survival were assessed by Kaplan-Meier curves, performing a sub analysis by MELD <25 vs. ≥25. Results: The cohort was 97% female and had a median age of 52 years old, median MELD of 25 (18–27) and Child-Pugh 11. Cirrhosis was confirmed in 58% of pts and fulminant hepatitis with hepatic submassive necrosis in 15%. Twenty seven pts (82%) began steroids treatment and 6 pts (18%) received LT without further therapy. In the treated group, 18 pts (67%) evolved with complete response, 4 pts (14.8%) with partial response and 5 pts (18.5%) with failure: 2 pts died (7%) by bacterial infection and 3 pts (11%) required rescue LT. MELD, cholesterol and histological severity were significantly associated with steroids treatment failure. After a median of 2 years of follow-up, 22 pts (67%) remained alive with steroid, 9 pts (27%) required LT and 3 pts (6%) died (one post LT). In the whole cohort, overall survival and free LT survival were 90% and 62.5% at 5 years and according to MELD (<25 vs. ≥25): 100% vs. 80% ( p = 0.09) and 85% vs. 41% ( p = 0.001) respectively. In the steroid-treated group overall survival and free LT survival at 5 years were 92% and 77.5% and according to MELD (<25 vs. ≥25): 100% vs. 82% (p = 0.1) and 90% vs. 60% ( p = 0.08) respectively. Conclusions: The high rates of survival and rescue found in our results endorse the need to prioritize the use of steroids in pts with acute jaundiced AIH. Even those with more severe disease (MELD > 25) in which the efficacy and tolerability of steroids is lower, we still found an excellent overall survival. SAT-378 CHANGES IN NUCLEAR RECEPTOR EXPRESSION INDUCED BY CHOLESTASIS IN MOUSE LIVER CELLS E. Gonzalez-Sanchez1, D. Firrincieli 1, C. Housset1, N. Chignard1. 1 Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S 938, CdR Saint-Antoine, Paris, France E-mail: [email protected] Background and Aims: Nuclear Receptors (NRs) are central regulators of liver pathophysiology, and are thus considered promising therapeutic targets in cholestatic disorders. As nonparenchymal liver cells play critical roles in cholestasis, changes in NR expression in these cells could contribute to the hepatic adaptative metabolic response in cholestatic disorders. Thus, our aim was to analyze NR expression profile in parenchymal and nonparenchymal liver cells in acute and chronic cholestatic liver injury. Methods: C57BL/6J male mice subjected to 72 h bile duct ligation were used as a model of acute cholestasis. Mdr2−/− male mice were investigated as a model of chronic cholestasis. Parenchymal and nonparenchymal liver cells (Kupffer cells, endothelial cells, biliary epithelial cells, BECs, and hepatic stellate cells, HSCs) were isolated

by mechanical and/or enzymatic methods and NRs expression was determined by RT-QPCR. Results: >NRs of the “bile acids and xenobiotic metabolism” and “lipid metabolism and energy homeostasis” physiological clusters are the most highly expressed in liver. Among these NRs, Pxr, Car and Shp presented low expression levels in non-parenchymal liver cells compared with total liver, whereas Fxr expression in HSCs was markedly higher and dramatically reduced in both acute and chronic cholestasis. Vdr, which basal RNA levels in liver were virtually undetectable, was highly expressed in non-parenchymal liver cells and further up-regulated in chronic cholestasis. Ppar-delta expression was higher in non-parenchymal cells than in total liver. Highest levels of Ppar-delta expression were detected in BECs and HSCs and its expression was reduced in both cell types in acute and chronic cholestasis. Besides modifications in NRs involved in hepato-biliary homeostasis, cholestasis altered the expression of NRs belonging to different physiological clusters in non-parenchymal liver cells. Particularly, Nor-1 and Er-beta expression, was down-regulated in BECs and HSCs in both cholestatic settings, whereas Nur-77 was upregulated in both cholestatic disorders in endothelial cells but downregulated both in BECs and HSCs. Conclusions: In cholestatic disorders, modifications in NR expression in non-parenchymal cells differ from the alterations identified in total liver. These data highlight that NRs specifically expressed in nonparenchymal liver cells such as Vdr, Er-beta or Nor-1, may be potential underestimated therapeutic targets in acute and chronic cholestasis. SAT-379 GUT-LIVER AXIS IN CYSTIC FIBROSIS: LACK OF ASSOCIATION BETWEEN INTESTINAL INFLAMMATION AND LIVER DISEASE IN ADULT CYSTIC FIBROSIS PATIENTS AFTER LUNG TRANSPLANTATION E. Halilbasic1, K. Staufer2, D. Schmidt1, S. Schick1, A. Brichta1, P. Jaksch2, W. Klepetko2, H. Vogelsang1, M. Trauner1, L. Kazemi-Shirazi1. 1 Department of Internal Medicine III; 2Department of Surgery, Medical University of Vienna, Vienna, Austria E-mail: [email protected] Background and Aims: The pathogenesis of cystic fibrosis-related liver disease (CFLD) remains largely unclear. Recent experimental studies using animal models of CF support the role of intestinal inflammation in the development of liver disease. In addition, elevated fecal calprotectin, an established marker of intestinal inflammation, was associated with liver cirrhosis in pediatric CF patients. The aim of this study was to test the role of intestinal inflammation in the development of hepatobiliary alterations in adult lung-transplanted CF patients. Methods: 36 lung-transplanted CF patients (all with pancreatic insufficiency, age 34 ± 8 y, 42% male) attending our outpatient clinic were tested for intestinal inflammation by measuring of fecal calprotectin and serum antisaccharomices cerevisiae antibodies (ASCA). Intestinal infection was excluded by stool cultures, celiac disease by negative EMA/TTG antibodies. Glucose-H2 breath test was performed to diagnose small intestinal bacterial overgrowth (SIBO) (n = 25). After exclusion of other causes of liver disease, CFLD was diagnosed by laboratory tests and ultrasound according to criteria of Debray et al. Magnetic resonance cholangiopancreaticography (MRCP) with Primovist® (n = 30) and transient elastography (TE) (n = 32) using FibroScan® were performed. Results: Fecal calprotectin was increased (cut off 100 μg/g stool) in 78% of patients (median 179 μg/g; IQR 148–297). 86% of patients were positive for either IgG (69%, median 42 U/mL; IQR 29.3–53.9) or IgA (67%, median 32.1 U/mL; IQR 17.6–45.7) ASCA. 12 of 25 (48%) patients presented with SIBO. 89% of patients had CFLD. 10 of 30 (33%) patients showed bile duct alterations in MRCP. There was no difference in markers of intestinal inflammation between patients with and without biliary alterations (median calprotectin 150 vs. 164 μg/g stool, median ASCA IgG 36.1 vs. 27.8 U/mL, median ASCA IgA 32.1 vs. 17.2 U/mL). Median liver stiffness was 4.5 kPa (IQR 3.6–5.3)

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POSTER PRESENTATIONS suggesting no or minimal fibrosis in majority of the patients. Only 4 (12.5%) patients presented with high-grade fibrosis (>10 kPa). There was no correlation of fecal calprotectin, serum ASCA IgG and IgA levels with serum liver enzymes or liver stiffness. Conclusions: The majority of adult lung-transplanted CF patients showed elevated markers of intestinal inflammation. Lack of association between intestinal inflammation and liver injury found in this study weakens the role of gut-liver axis in the pathophysiology of CFLD in adults after lung transplantation. SAT-380 HUMAN LEUCOCYTE ANTIGEN ASSOCIATIONS IN IGG4-RELATED DISEASE AND PRIMARY SCLEROSING CHOLANGITIS STRATIFIED BY IGG4 LEVELS, IN A MULTICENTER UK COHORT E.L. Culver1–3, J.M. Hurst4, T. Cargill1, D. Joshi5, M. Nayar6, M. Huggett7, K. Oppong6, S. Savic8, A. Bateman9, R.W. Chapman10, G.J. Webster11, E. Barnes2. 1Translational Gastroenterology Unit, John Radcliffe Hospital; 2Peter Medawar, Oxford University, Oxford; 3Hepatology, Royal Free Hospital, London; 4Peter Medawar Building, Oxford University, Oxford; 5Hepatology, Kings College London, London; 6 Hepatopancreatobiliary, Freeman Hospital, Newcastle; 7 Hepatopancreatobiliary; 8Rheumatology, St James Hospital, Leeds; 9 Histopathology, Southampton General Hospital, Southampton; 10 Hepatology, John Radcliffe Hospital, Oxford; 11University College London, London, United Kingdom E-mail: [email protected] Background and Aims: IgG4-related disease (IgG4-RD) is immunemediated as evidenced by tissue IgG4+plasma cells and CD4+T-cells, elevated serum IgG4 and a dramatic response to corticosteroids. Primary sclerosing cholangitis (PSC) is difficult to distinguish from biliary IgG4-RD, especially in those with an elevated IgG4 (PSC-high IgG4) that occurs in 9–18% of cases and has a more severe clinical course. Genetic associations in PSC have been defined in genomewide studies, however these were not stratified by serum IgG4. Genetic associations in IgG4-RD in Western populations are unexplored. We aimed to identify HLA allele frequencies to discriminate IgG4-RD from PSC, stratified by IgG4, in a multi-centre UK study. Methods: Serum IgG4 levels and HLA class I/II allelic frequency were determined in 113 IgG4-RD patients, 80 PSC patients (25 PSChigh IgG4, 55 PSC-normal IgG4) and 656 healthy controls from seven UK centres. We compared (i) All patients with high serum IgG4 to those with normal IgG4 (ii) IgG4-RD and PSC to healthy controls (iii) PSC-high IgG4 to PSC-normal IgG4 (iv) IgG4-RD to PSC (high and normal IgG4). Statistical analysis was performed using the Fisher’s exact test within multivariate and stepwise logistic regression models, and a Bonferroni correction applied to adjust for multiple comparisons. Results: Overall HLA-DRB1*0301 was more prevalent in patients with high serum IgG4 compared to normal serum IgG4 groups ( p < 0.001). IgG4-RD patients had a higher frequency of DRB1*0301 ( p < 0.001) and DQB1*0201 ( p = 0.01) compared to healthy controls. PSC patients had a higher frequency of DRB1*0301, B*0801 and C*0701 (all p < 0.001) compared with healthy controls, supporting European genome-wide studies. However, the DQB1*0301 allele ( p = 0.01) was more common in PSC-high IgG4 compared to PSC-normal IgG4 patients. IgG4-RD patients had a lower frequency of DQB1*0301 allele ( p < 0.05) than PSC-high IgG4 but no significantly different allele frequencies compared to PSC-normal IgG4. Conclusions: HLA class I/II alleles are associated with IgG4-RD in Western populations, suggesting an HLA-mediated component to disease pathogenesis. The DRB1*0301 allele is enriched in both IgG4 and PSC populations but additional alleles and stratification by IgG4 levels may discriminate between these conditions. Larger international genetic studies of IgG4-RD will improve the resolution of genetic analysis to identify important biomarkers of disease. S646

SAT-381 IMMUNOGLOBULIN E, EOSINOPHILS AND MAST CELLS IN ATOPIC INDIVIDUALS PROVIDE NOVEL INSIGHTS IN IGG4-RELATED DISEASE E.L. Culver1–3, R. Sadler4, A. Bateman5, M. Makuch6, B. Ferry4, R. Aalberse6, E. Barnes2, T. Rispens6. 1Translational Gastroenterology Department, John Radcliffe Hospital; 2Peter Medawar, Oxford University, Oxford; 3Hepatology, Royal Free Hospital, London; 4Clinical Immunology, Churchill Hospital, Oxford; 5Histopathology, Southampton General Hospital, Southampon, United Kingdom; 6Immunopathology, Sanquin Institution, Amsterdam, Netherlands E-mail: [email protected] Background and Aims: IgG4-related disease (IgG4-RD) is characterised by elevated serum IgG4 levels and tissue infiltration with abundant IgG4+plasma cells. IgG4 responses are often associated with IgE-mediated allergy. IgE and IgG4 antibodies are induced by Th2-cytokines, and Th2-cell-dominant immune responses are increased in IgG4-RD. We aimed to (i) define the prevalence of IgE antibodies in the blood and tissue of IgG4-RD patients and controls (ii) determine the utility of serum IgE in diagnosis of IgG4-RD and non-IgG4-RD controls with elevated IgG4 levels (iii) investigate the relationship of IgE with allergy/atopy, eosinophils and Th2 cytokines in IgG4-RD. Methods: Total serum IgG4, IgE and eosinophil counts were measured in a prospective cohort of 48 IgG4-RD patients, 42 disease controls with elevated serum IgG4 and 51 healthy donors. Clinical history of allergy and/or atopy was established and an immunoblot assay performed to measure IgE-specific responses to allergens. Luminex assays measured plasma Th2-cytokines. Histological immunostaining for IgE in active IgG4-RD tissues was performed. Spearman’s Rank (R) and ROC curves were calculated. Results: Serum IgG4 (>1.4 g/L) and IgE (>125 KUL) levels were elevated in 81.3% and 54.2% of IgG4-RD, both more prevalent than healthy controls ( p < 0.0001). Peripheral blood eosinophilia was present in 37.5% IgG4-RD versus 8.6% of healthy controls ( p = 0.004). There was a correlation between serum IgE and IgG4 (R0.46; p = 0.001), IgG (R0.32; p = 0.028) and eosinophil count (R0.45; p = 0.001). Tissue eosinophilia was present in 27% and IgE+ mast cells were abundant (>10/HPF) in 50% of IgG4-RD tissue specimens. Serum IgE concentrations were higher in IgG4-RD (median 323 KU/L) than non-IgG4-RD with elevated IgG4 (median 55.7 KU/L) ( p < 0.01) Serum IgE of 689 KU/L (5.7 × ULN) had a specificity of 92.9% and likelihood ratio of 3.59 to distinguish IgG4-RD from non-IgG4-RD with elevated IgG4. Clinical history of allergy/atopy was present in 62.5% IgG4-RD versus 17% healthy controls ( p < 0.001). IgE-mediated allergen-specific response was identified in 39.6% (19/48) of symptomatic IgG4-RD. Serum IgE was higher in those with allergy/atopy than in those without ( p = 0.031), although there was no significant difference in Th2-plasma cytokines. Conclusions: In a subset of IgG4-RD patients with a history of allergy/ atopy, an elevated serum IgE level and the presence of IgE+ mast cells in involved tissues supports the role of a Th2-milieu and perhaps evidence of an IgE-mediated response. SAT-382 AN EARLY DEFINITION OF RESPONSE TO CORTICOSTEROIDS IN ACUTE SEVERE AUTOIMMUNE HEPATITIS F. Saffioti1, E. Culver1, A. Marshall1, D. Patch1, J. O’Beirne1, D. Thorburn1, R. Westbrook1. 1Royal Free Hospital, Sheila Sherlock Liver Centre, London, United Kingdom E-mail: [email protected] Background and Aims: Acute severe presentations of autoimmune hepatitis (AS-AIH) provide challenges with regard to diagnosis and treatment. Steroid administration can be lifesaving and avoid the need for liver transplantation (LT) in those patients who respond; in non-responders they can increase risk of sepsis and peri-LT morbidity

Journal of Hepatology 2016 vol. 64 | S631–S832