F. Saffioti

Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.

There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well‐characterized large‐duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992‐2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008‐2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases‐1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant‐free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73‐0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4‐2.5, and 1.5, 95% CI 1.1‐2.1, respectively) was associated with transplant‐free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1‐1.6, and 1.6, 95% CI 1.2‐2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments. Conclusion: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score. (Hepatology 2015;62:188‐197)

Development and Regression of Cirrhosis

Liver cirrhosis is the ultimate consequence of the wound healing reaction subsequent to a chronic injury, which leads to a complete derangement of the normal hepatic lobular and vascular architecture. Cirrhosis is characterized by patterns of evolution depending on the causative agent and a series of complex underlining mechanisms in which neo-angiogenesis and necro-inflammation play a key role. The importance of the different cell types involved and of the extracellular matrix composition as well as the role of innate immunity, bacterial translocation and oxidative stress are also emerging. A variable degree of regression of fibrosis and even cirrhosis has been described, in experimental models, after suspension of the liver disease causative agent. As some individual features influence the rate of fibrosis progression, genetic and epigenetic factors are likely to influence fibrosis regression. Key Messages: There is increasing awareness that cirrhosis is not a static condition but a dynamic process. Current semi-quantitative scores and clinical classifications are inaccurate and unable to identify the different phases of evolution of the advanced stages of chronic liver diseases (CLDs). The increasing availability of effective etiology-driven therapeutic options for CLDs makes reversion of cirrhosis a more possible prospective. However, the removal of the causing agent, depending on the stage of the disease, does not necessarily eliminate the risk of disease progression, decompensation and development of hepatocellular carcinoma. Also, the non-invasive markers currently validated for the assessment of fibrosis are not suitable for an effective evaluation of fibrosis regression. Conclusions: There is a critical need of a system that would be able to more accurately describe the dynamic development of cirrhosis and the impact of tissue fibrosis, neo-angiogenesis, necro-inflammation and attempted regeneration on its evolution. Effective treatment of CLD can lead to a variable degree of fibrosis regression. New markers able to evaluate this process will need to be detected and validated.

MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation

Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune‐mediated liver damage. In this study, we addressed the question whether mucosal‐associated invariant T (MAIT) cells, innate‐like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon‐γ (IFN‐γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA‐DR, and CTLA‐4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)‐12 and IL‐18, leading to decreased IFN‐γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL‐12 further resulted in expression of the profibrogenic cytokine IL‐17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL‐17. Conclusion: Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC‐mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172‐186).

Non-invasive Prediction of High-risk Varices in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

BACKGROUND: Baveno-VI guidelines recommend that patients with compensated cirrhosis with liver stiffness by transient elastography (LSM-TE) <20 kPa and platelets >150,000/mm3 do not need an esophagogastroduodenoscopy (EGD) to screen for varices, since the risk of having varices needing treatment (VNT) is <5%. It remains uncertain if this tool can be used in patients with cholestatic liver diseases (ChLDs): primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These patients may have a pre-sinusoidal component of portal hypertension that could affect the performance of this rule. In this study we evaluated the performance of Baveno-VI, expanded Baveno-VI (LSM-TE <25 kPa and platelets >110,000/mm3), and other criteria in predicting the absence of VNT. METHODS: This was a multicenter cross-sectional study in four referral hospitals. We retrospectively analyzed data from 227 patients with compensated advanced chronic liver disease (cACLD) due to PBC (n = 147) and PSC (n = 80) that had paired EGD and LSM-TE. We calculated false negative rate (FNR) and number of saved endoscopies for each prediction rule. RESULTS: Prevalence of VNT was 13%. Baveno-VI criteria had a 0% FNR in PBC and PSC, saving 39 and 30% of EGDs, respectively. In PBC the other LSM-TE-based criteria resulted in FNRs >5%. In PSC the expanded Baveno criteria had an adequate performance. In both conditions LSM-TE-independent criteria resulted in an acceptable FNR but saved less EGDs. CONCLUSIONS: Baveno-VI criteria can be applied in patients with cACLD due to ChLDs, which would result in saving 30–40% of EGDs. Expanded criteria in PBC would lead to FNRs >5%.

PWE-096 Non-invasive assessment of disease severity in primary sclerosing cholangitis (psc): clinical scores, transient elastography (te) and the enhanced liver fibrosis (elf) test

Introduction In PSC it has been believed that staging fibrosis is unhelpful due to the patchy nature of the condition, hence liver biopsy is rarely performed. Emerging data indicates that TE correlates well with fibrosis stage on liver histology and that both TE and the ELF test provide prognostic information in PSC. Thus far there has been no direct comparison of ELF testing and TE. Here we present a comparison of clinical scores, TE and the ELF test in patients with PSC. Method Patients with large-duct PSC had TE [Fibroscan® (Echosens): 10 valid measurements and a success rate >60% after 3 hrs fasting] and serum stored at the same visit to the Royal Free, London and the Hospital Clínic, Barcelona (Jun 2010–Feb 2015). Full patient demographics and clinical outcomes were recorded. Clinical scores of disease severity (APRI and Mayo risk score) were obtained on the day of assessment. Stored sera were tested for ELF [ADVIA Centauro® XP system (Siemens Diagnostics). Spearman–s rank correlation was used due to the non-normal distribution of measures. Results 39 [1 autoimmune overlap, 28(72%) male] PSC patients [mean (±SD): age 50(±14) yrs; age at diagnosis 42(±14) yrs; time from diagnosis of 7.8(±7.1) yrs] were evaluated. 28 patients (80%) were diagnosed with IBD: 21 ulcerative colitis, 6 Crohn’s disease, 1 indeterminate colitis. There were no significant differences in ELF, TE or age between UK and Barcelona patients. Fibroscan correlated with ELF with a Spearman–s rho 0.676 p < 0.001. Similarly, a strong correlation for both ELF and Fibroscan with Mayo [rho 0.836 (p < 0.001) and rho 0.771 (p < 0.001), respectively] and APRI [rho 0.766 (p < 0.001) and rho 0.755 (p < 0.001), respectively] scores was found.Abstract PWE-096 Table 1 Correlations between Fibroscan®, ELF test and other prognostic scores in PSC patients Fibroscan® ELF®Test Rho P value Rho P value APRI score (AST/PLTs) 0.755 <0.001 0.766 <0.001 Mayo score 0.771 <0.001 0.836 <0.001 ELF®Test 0.676 <0.001 – – Conclusion A significant correlation between liver stiffness measured by TE, ELF test, APRI and Mayo risk score is here demonstrated for the first time in patients with PSC. Our results suggest that while the process of fibrosis progression in PSC is poorly understood, non-invasive tests validated in other chronic liver diseases perform consistently in patients affected and should be further evaluated as tools for staging the disease, monitoring disease progression and prognosis and may provide much needed surrogate end points for clinical trials in PSC. Disclosure of interest F. Saffioti: None Declared, M. Vesterhus: None Declared, A. Telese: None Declared, G. Mazza: None Declared, D. Roccarina: None Declared, M. Rosselli: None Declared, W. Jonasson: None Declared, A. Parés: None Declared, T. Karlsen: None Declared, W. Rosenberg: None Declared, M. Pinzani: None Declared, A. Marshall: None Declared, D. Thorburn Grant/Research Support from: Boston Scientific to fund a clinical research fellow.