Fabio Marra Dipartimento di Medicina Sperimentale e Clinica University of Florence, Italy
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1 I tests biochimici nella valutazione dell infiammazione e fibrosi epatica Fabio Marra Dipartimento di Medicina Sperimentale e Clinica University of Florence, Italy fabio.marra@unifi.it
2 Abbvie: consultant fees Allergan: consultant fees Alfa-Wassermann: travel grants AstraZeneca: consultant fees Bayer: speaker honoraria, consultant fees, travel grants Gilead: speaker honoraria, consultant fees Intercept: speaker honoraria Menarini: consultant fees
3 Diagnostic approaches to chronic liver disease Biopsy Imaging Biomarkers Biopsy Elastography HVPG
4 Defnitions of biomarkers
5
6 Use of biomarkers in Hepatology Yesterday: Grade and stage the damage in hepatitis C and B to identify candidates to treatment (Peg+Riba DAA first wave ) Today: Identify patients with NASH (ASH?) at higher risk of progression Noninvasive diagnosis of portal hypertension Stratification of the risk of hepatocellular carcinoma in patients with cirrhosis
7 What have we learned from HepC?
8 Progression of chronic liver diseases F0 F1 F2 F3 F4 No fibrosis Fibrosis without septa Few septa Numerous Septa W/O cirrhosis Numerous Septa WITH CIRRHOSIS SIGNIFICANT FIBROSIS CIRRHOSIS Deranged microvascular anatomy Portal hypertension Cancer
9 Gressner et al., World J Gastroenterol 2009; 28:2433
10 Available serum markers of fibrosis Indirect markers Direct markers Combination markers
11 EASL CPG, 2015
12 EASL CPG, 2015
13 Biomarkers vs. FibroScan Biomarkers FibroScan Advantages: Good reproducibility High applicability Low cost (non-patented) Disadvantages: Liver non-specific More limited performance for cirrhosis Cost (patented) Advantages: Measures a property of liver High performance in cirrhosis User-friendly Disadvantages: Low applicability (80%) False positive (fat, inflammation) Requires a dedicated device
14 Poor classification of intermediate stages by non-invasive tests Cales et al., Liver Int 2008;28:1352
15 SAFE biopsy for significant fibrosis (> F2) Castera et al., J Hepatol 2010;52:191
16 Patient outcome as a reference standard Vergniol et al., Gastroenterology 2011;140:1970
17 The need for a dynamic marker to assess inflammation and fibrosis in clinical practice 1. Not for cross-sectional staging or diagnosis 2. Sensitive to rapid changes inactivity and/or fibrogenesis and/or fibrolysis 3. Possibly related to ECM turnover 4. Specific for a given chronic liver disease
18 The current problem: NAFLD
19 Challenges in the management of NASH Understand the pathogenesis guided approach Stratify the patients at risk of different metabolic complications Identify those who are likely to progress to cirrhosis Set up meaningful clinical trials
20 Rinella, JAMA 2015
21 Global prevalence of NAFLD Younossi & Henry Gastroenterology 2016
22 Ultrasound and NAFLD Sensitivity: US = 100% CT = 93% but when fat is > 33% DOES NOT DISCRIMINATE NAFLD FROM NASH Saadeh et al., Gastroenterology 2002; 123:745
23 NAFLD in patients with normal ALT Mofrad et al., Hepatology 2003;37:1286
24 Analysis of large series or of the general population: the Fatty Liver Index An algorithm based on: BMI Waist circumference Triglycerides GGT FLI>60: likelihood>78% presence FL FLI<20: likelihood>91%absence of FL Bedogni et al., BMC Gastroenterology 2006; 6:33
25 Fatty Liver index (FLI) in the Cremona study Calori et al., Hepatology 2011;54:145
26 Rinella, JAMA 2015
27 Non-imaging tests for the diagnosis of NASH Bedossa & Patel, Gastroenterology 2016
28 CK-18 as a biomarker of NASH and fibrosis Feldstein et al., Hepatology 2009;50:1072
29 A serum marker algorithm for the diagnosis of NASH Shen et al., J Hepatol 2012
30 Performance of CK-18 in the diagnosis of NASH Cusi et al., J Hepatol 2014
31 Inflammation and immunity in obesity Lumeng, JCI 2011
32 Functions of Drosophila s fat body Sensing energy and nutrient availability Coordination of metabolic responses Coordination of the response to pathogens
33 Adipose tissue changes after weight gain FFA Treg TNF- IL-1 CCL2 OPN inos Adipose tissue IR Lipolysis M1 Leptin Adiponectin CCL2 M1 M2 Weight gain M2 Treg Apoptosis Hypoxia Marra & Lotersztajn, Curr Pharm Des 2013
34 ADIPOKINES: cytokines of the adipose tissue Metabolic control Leptin Adiponectin Resistin (rodents) Visfatin Retinol binding protein 4 Apelin Vaspin Omentin Chemerin Acylation stimulating protein Agouti signaling protein Marra & Bertolani, Hepatology 2009;50:957 Inflammation Resistin (humans) Tumor necrosis factor IL-6 IL-1 IL-10 IL-1 receptor antagonist Monocyte chemoattractant protein-1 (CCL2) RANTES (CCL5) IL-8 (CXCL8) Interferon.inducible protein-10 (CXCL10) Migration inhibitory factor (MIF) Hepcidin Adipsin Serum amyloid protein A Tissue repair Angiotensinogen Renin Plasminogen-activator inhibitor-1 (PAI-1) Nerve growth factor Vascular endothelial growth factor Transforming growth factor-β Hepatocyte growth factor (HGF) Heparin-binding, epidermal growth factor-like growth factor (H-EGF) Insulin-like growth factor-1 Tissue factor
35 Chemokines and NASH progression Marra & Tacke, Gastroenterology 2014
36 Adipokine groups potentially involved in fibrosis Acute phase proteins CRP, serum amyloid A, PAI-1, haptoglobin Cytokines TNF-, IL-6, IL- 10, IL-R1a, TGF ), Chemokines MIP-2, CCL2, CCL5, CXCL8, CXCL10 Proinflammatory factors leptin, resistin, activin,osteopontin, chemerin, WNT5A Anti-inflammatory factors adiponectin, SRFP5, omentin, ghrelin, lipocalin-2 DAMPS tenascin C, calprotectin, HSP- 72, HMGB1
37 New biomarkers in NASH Ajmera et al., Hepatology 2017
38 Anstee, Nat Rev Gastro 2013
39 Pink Floyd, 1975
40 Rinella, JAMA 2015
41 Fibrosis stage and mortality Dulai et al., Hepatology 2017
42 EASL CPG, J Hepaotol 2016
43 Bugianesi et al., J Hepatol 2016
44 Screening for NAFLD in patients with diabetes: the Edinburgh study Morling et al, J Hepatol 2014
45 Liver fibrosis in the general population Gines et al., Lancet G&H 2016
46
47 Risk of fibrosis in relatives of patients with NASH-cirrhosis Caussy et al., JCI 2017
48 Major pathways involved in NASH pathogenesis Gentilini et al., Curr Mol Med 2016
49 The future of biomarkers
50 Extracellular vescicles Szabo et al., Nat Rev G&H 2017
51 Exosome composition Szabo et al., Nat Rev G&H 2017
52 EV and liver pathophysiology Maji et al., AJP GI Liver 2016
53 Microparticles as biomarkers of inflammation Kwong et al., Nat Biotechnol 2013
54 Epigenetic mechanisms of gene regulation Moran-Salvador & Mann CMGH 2017
55 mirna in NAFLD Baffy, J Clin Med 2015
56 Methylated DNA as a biomarker Hardy et al., Gut 2016
57 Targeted Imaging of Fibrogenesis and Fibrosis Schuppan et al., J Hepatol 2012
58 Big data as a source of targets and biomarkers Zhang et al., Gut 2016
59
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