Liver fibrosis: Twenty years after. Fabio Marra Dipartimento di Medicina Sperimentale e Clinica Università di Firenze

Transcription

1 Liver fibrosis: Twenty years after Fabio Marra Dipartimento di Medicina Sperimentale e Clinica Università di Firenze fabio.marra@unifi.it

2 DISCLOSURES: Grants from: ViiV Healthcare Consultant for: Bayer Abbott

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4 Cirrhosis and fibrosis are different Role of extracellular matrix Genetic and epigenetic predisposition Multiple types of injury result in fibrosis NAFLD is a cause of fibrosis and cirrhosis Duckworth, BMJ 1892

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6 Significance

7 What is the meaning of hepatic fibrosis? A dynamic, multicellular, integrated, (partially) reversible chronic wound healing process Injury Inflammation Repair Regeneration

8 Liver Fibrosis: a Dynamic Path Viral Hepatitis Fibrosis Stage Phase of slow progression SIGNIFICANT FIBROSIS Phase of rapid progression Alcohol NASH Time (and patient s age)

9 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 Deranged microvascular anatomy Portal hypertension Cancer

10 Patterns of fibrosis development Viral Biliary Vascular ASH/NASH

11 Fibrosis quantity and distribution depend on etiology Measurement of Collagen Proportionate Area (CPA) Hall A. et al., Histopathology 2012; 60:

12 Hepatic fibrosis develops with different morphological and spatial patterns Etiology has a relevant impact on disease progression (fibrogenesis) and regression (fibrolysis) Cirrhosis is not simply a lot of fibrosis

13 Significance Pathogenesis

14 Mechanisms of fibrogenesis and fibrolysis Mallat & Lotersztajn, Am J Physiol Cell Phys 2013

15 Cellular players in fibrosis Schuppan et al., J Clin Invest 2013

16 Origin of fibrogenic cells Mallat & Lotersztajn, Am J Physiol Cell Phys 2013

17 Miller, AJP Renal 2011 Mederacke et al., Nat Commun 2013

18 All Roads lead to fibrosis ASH AIH NASH HCV Iron HIV coinfection HBV Vascular Biliary

19 Different mechanisms of fibrogenesis in chronic liver diseases Viral, Autoimmune Inflammation ASH, NASH Cholestatic Morphogens

20 HIV gp120 Inflammatory/fibrogenic activity PBMCs HSCs Inflammation mir29b downregulation fibrogenesis IL-1β activation Kaul et al., Nature 2001

21 Diagnosis Significance Pathogenesis

22 Diagnostic approaches to staging Biopsy Imaging Biomarkers Biopsy Elastography HVPG

23 Available serum markers Indirect markers APRI Fibrotest Fib-4 Direct markers Hyaluronic acid ELF panel Combination markers Hepascore

24 General considerations on serum markers of fibrosis Minimal (F0-F1) vs. significant ( F2) fibrosis: Detection of advanced ( F3) fibrosis: Detection of cirrhosis: Stepwise differentiation of fibrosis stages: Fibrogenic process monitoring:

25 Poor classification of intermediate stages by non-invasive tests Cales et al., Liver Int 2008;28:1352

26 Genes instead of biochemical markers? Gary Larson

27 A 7 gene signature identifies the risk of developing cirrhosis during chronic hepatitis C Huang et al., Hepatology 2007;46:297

28 Transient elastography (Fibroscan ) Based on a ultrasound transducer probe mounted on the axis of a vibrator. Vibrations induce an elastic shear wave that propagates through the underlying liver tissue. The velocity of the wave is directly related to tissue stiffness and to the amount of fibrotic tissue Tests approximately 1/500 of the liver Acoustic radiation force impulse (ARFI) MR elastography

29 Multilevel likelihood ratios for the prediction of significant fibrosis, and cirrhosis Likelihood ratios above 10 and below 0.1 provide strong evidence to rule in or rule out diagnoses, respectively. Arena et al., Gut 2008;57;1288

30 FIBROscan or HEPATOscan? Confounding factors: Disease inflammatory activity Tissue edema Extrahepatic cholestasis Passive congestion Active blood flow (meal)

31 A fight between invasive and non-invasive tools?

32 Schuppan & Afdhal, Lancet 2008;371:838

33 Patient outcome as a reference standard Vergniol et al., Gastroenterology 2011;140:1970

34 Advantages Characteristics of Liver Biopsy Direct Well-established staging system Diagnosis of other form of liver disease Evaluation of histological activity and degree of steatosis Measurement of collagen proportionate area Disadvantages Invasive Painful (10-30%) Semi-quantitative estimate Sampling error Understaging (20%) Small but significant risk of complications Contraindications Adequacy At least 25 mm in length and including at least 11 portal tracts Modified from: Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95

35 Biopsy Clinical evaluation Patient categorization CLINICAL DECISION Imaging Serum markers Fibroscan Follow-up with noninvasive markers Unstable Repeat biopsy Stable

36 Diagnosis Significance Treatment Pathogenesis

37 Translational research and the development of an antifibrogenic drug Molecular plausibility In vitro actions Effects in in vivo models Safety/tolerability Clinical trials Use in clinical practice

38 Virus, Ethanol, Iron, Autoimmunity, Fat, Biliary damage Treat the primary disease: Interferon/Ribavirin Nucleos(t)ide analogs Abstinence from alcohol Venesection (HH) Immunosuppression Weight loss & physical activity Biliary decompression Damage

39 Inflammation Corticosteroids Chemokine antagonists Virus, Ethanol, Iron, Autoimmunity, Fat, Biliary damage Oxidative stress Apoptosis Antioxidants Herbal medicines (curcumin) UDCA Caspase inhibitors Hepatic Growth Factor (HGF) Cytokine secretion Damage Pentoxifylline Decoy receptors MAb

40 Problems with trials of antifibrotic drugs Clinical benefit requires a long period of time Competition with antiviral agents Requirement for liver biopsy Efficacy may not be assessed by a simple test which allows short pilot trials Difficulties in measuring the endpoint Identification of patients more likely to respond

41 The need for a dynamic serum marker to assess fibrosis in clinical practice 1. Not for cross-sectional staging or diagnosis 2. Sensitive to rapid changes in fibrogenesis and/or fibrolysis 3. Possibly related to ECM turnover 4. Specific for a given chronic liver disease

42 Targeted Imaging of Fibrogenesis and Fibrosis Schuppan et al., J Hepatol 2012

43 Dynamic changes in LSM and prognosis Corpechot et al., Gastroenterology 2014

44 Changes in serum markers predict survival in CHC Vergniol et al., Hepatology 2014

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46 The next ten years Talking to the liver from the outside

47 FFA Adipokine imbalance Inflammatory cytokines Bacterial products Specific nutrients Kupffer cells Inflammatory cells TNF IL-1β CCL2 TGF-β ROS JNK NF-κB ER stress Hep HSC Fibrosis Rosselli et al, Curr Pharm Des 2014

48 Adipose tissue changes after weight gain FFA Treg TNF-α IL-1β 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

49 DAMPs LPS LTA PGN Toll-like Pattern recognition receptors Activation of KC and inflammatory cells MCP-1 TGF-β Hepatic stellate cells TLR4 TLR2 PGRP-L CD14 PGRP-S Paik et al., Hepatology 2003;37:1043 Brun et al., AJP-GI : G571 Seki et al. Nat Med 2007;13:1324

50 Dysbiosis contributes to liver fibrosis CTRL (HFD FLORA) HFD (CTRL FLORA) SHAM CTRL (HFD FLORA) HFD (CTRL FLORA) BDL De Minicis et al., Hepatology, 2014

51 Nutrients and fibrosis We are what we eat

52 Nutrients, liver injury and fibrosis Coffee Saturated FA Lipotoxicity ROS Inflammation LPS Fructose Steatosis AGE n-3 PUFA Cholesterol Modified from Marra & Lotersztajn, Curr Pharm Des 2013

53 The next ten years Talking to the liver from the outside Regeneration and stem cell biology

54 Progenitor cells and fibrogenesis Williams et al., Gastroenterology 2013

55 The next ten years Talking to the liver from the outside Regeneration and stem cell biology Cancer

56 Microenvironment and HCC Hernandez-Gea et al., Gastroenterology 2013

57 The next ten years Talking to the liver from the outside Regeneration and stem cell biology Cancer Cirrhosis

58 Cirrhosis F4

59 Paired liver biopsies following lamivudine therapy Kweon et al., J Hepatol 2001

60 Regression of fibrosis (and cirrhosis?) after Hep B therapy Marcellin et al., Lancet 2013; 381:486

61 Deranged microvascular anatomy in cirrhosis Normal liver Extensive FIBROSIS and conversion of normal liver architecture into STRUCTURALLY ABNORMAL NODULES Cirrhotic liver Establishment of INTRAHEPATIC VASCULAR SHUNTS between afferent and efferent vessels of the liver B Onori et al., J Hepatol 2000; 33:555

62 Different End-points for Different Stages Extensive Regression Possible FIBROSIS REGRESSION Partial to Extensive Regression Possible PREVENT THE DEVELOPMENT OF CIRRHOSIS Limited Regression Possible REDUCE FIBROSIS IN CIRRHOTIC LIVER AND REDUCE PORTAL PRESSURE

63 Bruno et al., Hepatology 2010;51:2069

64 Towards a new classification of cirrhosis Arvaniti et al., Gastroenterology 2010;139:1246

65 Progression of Chronic Liver Disease Rosselli et al., Gut 2013

66 Cirrhosis sub-classification based on fibrosis Tsochatzis et al., J Hepatol 2014

67 Thanks! Paolo Gentilini Hanna E. Abboud Massimo Pinzani Giacomo Laffi Maurizio Parola Umberto Arena Stefano Milani Francesco Vizzutti