2 - Meccanismi fibrogenetici    e implicazioni cliniche              Fabio Marra       Dipartimento di Medicina Interna   ...
What is fibrosis?
What is the meaning of hepatic fibrosis?    The formation of excess fibrousconnective tissue in an organ or tissue in    a...
What is the meaning of hepatic fibrosis?    A dynamic, multicellular,integrated, (partially) reversiblechronic wound heali...
Patterns of fibrosis development Viral               Biliary Vascular            ASH/NASH
Key introductory concepts Hepatic fibrosis develops with differentmorphological and spatial patterns  The process involves...
How does fibrosis develop?
Fibrosis progression      Cohen-Naftaly and Friedman, Ther Adv Gastroenterol 2011
SL Friedman, 2008
The cell biology of hepatic fibrogenesis                           JP Iredale, J Clin Invest 2007; 117:539
Deposition of fibrillar                                 extracellular matrix                                 Inhibition of...
Mann & Marra, J Hepatol 2010
All Roads lead toFibros                           Rome!                          is     ASH        AIH      NASH HCV      ...
Effects of HIV on hepatitis C Enhanced HCV replication Decreased response rates to HCV treatment Faster progression of ...
Kim & Chung, Gastroenterology 2009;137:795
Effects of HIV-gp120 on hepatic stellate cells     HSC migration            Cytokine expression                           ...
HSC recruitment    HIV-infected cells                                                     via migration                   ...
All Roads lead toFibros                           Rome!                          is     ASH        AIH      NASH HCV      ...
Why fat?1. Severe obesity is associated with a greater   prevalence of NAFLD, NASH, and cirrhosis2. Alcoholic steatohepati...
Adipose tissue changes after weight gain                                  ↑FFA                           Adipose tissue IR...
Inflammation   ADIPOKINES: cytokines of the             Resistin (humans)                                            Tumor...
ResistinAdiponectin                         Leptin
Leptin                                                            Deposition of fibrillarProliferation/survival           ...
Abu-Shanab & Quigley, Nat RevGastroenterol Hepatol.2010; 7;691
Inflammasome deficiency worsens NASH     interacting with the microbiome                                     Innate immune...
Gut               Excess free                 LPS               fatty acids                              Bacterial        ...
The ‘multiple parallel hits’ hypothesis                         Tilg & Moschen, Hepatology 2010;52:1836
Genetic predisposition to fibrosis
Zimmer & Lammert, Best Pract Res Clin Gatsroenterol 2011
Zimmer & Lammert, Best Pract Res Clin Gatsroenterol 2011
Adiponutrin (PNPLA3) genotype is associated  with the severity of damage and fibrosis       NASH                       Fib...
GWAS of susceptibility to fibrosis in HepC                             Several susceptibility                             ...
Paternal epigenetic suppression of hepatic fibrosis in male progeny                             Zeybel et al., Nat Med 2012
Paternal epigenetic suppression of hepatic fibrosis in male progeny                             SL Friedman, Nat Med 2012
Pathways in fibrosis that promote HCC                          Zhang & Friedman, Hepatology 2012
How can we measure fibrosis in      clinical practice?
Progression of chronic liver diseases       F0          F1             F2             F3           F4                     ...
Notes from EASL clinical practice guidelines Assessment of the severity of hepatic fibrosis isimportant in decision makin...
Chronic liver diseases:Methods to establish disease progression                                         Imaging: US, CT, M...
Serum markers
Gressner et al., World J Gastroenterol 2009; 28:2433
Currently available serum markers       Indirect markers       Direct markers       Combination markers
Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
General considerations on      serum markers of fibrosis Minimal (F0-F1) vs. significant (≥ F2) fibrosis:                ...
Algorithms?
SAFE biopsy for significant fibrosis (> F2)                            Castera et al., J Hepatol 2010;52:191
The Castera algorithm for significant fibrosis                             Castera et al., J Hepatol 2010;52:191
Genes instead of biochemical markers?
A 7 gene signature identifies the risk ofdeveloping cirrhosis during chronic hepatitis C                               Hua...
Marcolongo et al., Hepatology 2009
Transient elastography
Transient elastography (Fibroscan®)                 Based on a ultrasound transducer               probe mounted on the ax...
AUCGRAY AREA
Multilevel likelihood ratios for the prediction of       significant fibrosis, and cirrhosisLikelihood ratios above 10 and...
Suspected Fibrogenic Liver Disease                       Transient elastography    ≤6 kPa             Intermediate values ...
Poor classification of intermediate  stages by non-invasive tests                           Cales et al., Liver Int 2008;2...
L. Castera, Gastroenterology 2012
In search for a better standard
Inaccuracy of biopsy affects marker perfomance   When errors in the diagnostic test and the gold      standard are indepen...
ELF test can predict clinical outcomes                             Parkes et al., Gut 2010;59:1245
Parkes et al., Gut 2010;59:1245
Vergniol et al., Gastroenterology 2011;140:1970
Predicting clinical outcomes with standard  laboratory tests in chronic hepatitis C                         Ghany et al., ...
Ghany et al., Gastroenterology 2010;138:136
What we would like to have from a non-              invasive tool1. Diagnostic accuracy >0.8 for advanced fibrosis2. Diagn...
Fibrosis Vs. Fibrogenesis                         Chronic HCV-Hepatitis        Collagen I                         HAI Scor...
The need for a ‘dynamic’ serum marker to   assess fibrosis in clinical practice1. Not for cross-sectional staging or diagn...
Role of biopsy in the management of             chronic hepatitis C  Contribution to staging in selected cases  Grading  A...
Liver Biopsy1. - Provides clues about etiology2. - Provides clues about cofactors3. - Allows immunohistochemical,   bioche...
Histological-hemodynamic correlations              in cirrhosis  Septal thickness      Nodule size                        ...
Morphometric analysis of advanced fibrosis  “In advanced chronic hepatitis C, fibrosis increases at a rapid        pace th...
Collagen area better correlates with HVPG than                 Ishak stage       Predictor of HVPG > 6 mm Hg       Ishak g...
Schuppan & Afdhal, Lancet 2008;371:838
Biopsy                      Patient   Biopsy                   categorization   Clinical    Clinical  evaluation  evaluati...
Present and future of HCV infection      F0                                             Decompensation           F1    F4 ...
Classification of chronic liver disease                           Garcia-Tsao et al., Hepatology 2010
Progression of CLD:           Key Pathophysiological Points                                                               ...
Assessment of fibrosis progression and      regression in different disease stages                                     HVP...
Splenic elasticity is a marker of portal            Hypertension                                Hirooka et al., Radiology ...
Progression of hepatitis C:         clinical needs for patient managementBeginning ofinfection            Predict and Moni...
Towards a new classification of cirrhosis                       Arvaniti et al., Gastroenterology 2010;139:1246
Does increased knowledge of pathogenesis translate into   antifibrotic therapies?
Virus, Ethanol, Iron,   Treat the primary disease:   Autoimmunity,                        Interferon/RibavirinFat, Biliary...
Inflammation                             Corticosteroids                             Chemokine antagonists                ...
Targeting hepatic stellate cell activation                 Interferon-γ               PPAR-γ agonists                Imati...
Limitation of matrix deposition                       Anti-TGF-β                       ColchicineApoptosis of activated st...
Antifibrotic drugs already in clinical use       Colchicine       Pentoxifylline       Canrenone       Statins       COX i...
Molecular plausibility   In vitro actions      Effects in in vivo models        Safety/tolerability           Clinical tri...
Problems with trials of antifibrotic drugsClinical benefit requires a long period of time‘Competition’ with antiviral agen...
Lessons from antifibrotic trials  Clinical benefits require a long period of time  Need for noninvasive markers  Quantitat...
Selection of patients for antifibrotic trialsEtiology:HCV or HBV: known natural historyNASH: several components for progno...
Progression of autoimmune hepatitis                    Hudacko & Thiese Arch Pathol Lab Med 2011
Changes in fibrillar matrix affects degradation            EARLY            FIBROSIS                       MMPs           ...
Deranged microvascular anatomy in cirrhosis               Extensive FIBROSIS and conversionNormal liver   of normal liver ...
Which is the best drug to test?1.   Easily administered2.   Tolerable for a long time3.   Safe and devoid of off-target ef...
Angiotensin receptor signaling predicts the                  response to losartan                      ATII-Racytoplasm   ...
Diagnostic endpoints   Biopsy: scored the right way and assessingfibrogenesis (e.g. alpha-SMA)   Serum tests   Elastograph...
Perspectives for antifibrotic therapies       Cell-based therapies       Gut microbiota/TLRs       Angiogenesis       Weig...
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®
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Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®

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Meccanismi fibrogenetici e implicazioni cliniche - Prof. F. Marra (Università di Firenze)
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Meccanismi fibrogenetici e implicazioni cliniche - Gastrolearning®

  1. 1. 2 - Meccanismi fibrogenetici e implicazioni cliniche Fabio Marra Dipartimento di Medicina Interna Università di Firenze fabio.marra@unifi.it
  2. 2. What is fibrosis?
  3. 3. What is the meaning of hepatic fibrosis? The formation of excess fibrousconnective tissue in an organ or tissue in a reparative or reactive process.
  4. 4. What is the meaning of hepatic fibrosis? A dynamic, multicellular,integrated, (partially) reversiblechronic wound healing process
  5. 5. Patterns of fibrosis development Viral Biliary Vascular ASH/NASH
  6. 6. Key introductory concepts Hepatic fibrosis develops with differentmorphological and spatial patterns The process involves resident, infiltrating,and distant cells Different molecular mechanisms underlyfibrosis development in different settings Fibrosis is NOT cirrhosis
  7. 7. How does fibrosis develop?
  8. 8. Fibrosis progression Cohen-Naftaly and Friedman, Ther Adv Gastroenterol 2011
  9. 9. SL Friedman, 2008
  10. 10. The cell biology of hepatic fibrogenesis JP Iredale, J Clin Invest 2007; 117:539
  11. 11. Deposition of fibrillar extracellular matrix Inhibition of matrix degradation Increased proliferation and survival Cell migrationQuiescent HSC Activated HSC Cell contraction Inflammatory cell recruitment Angiogenesis
  12. 12. Mann & Marra, J Hepatol 2010
  13. 13. All Roads lead toFibros Rome! is ASH AIH NASH HCV Iron HIV Vascularcoinfection HBV Biliary
  14. 14. Effects of HIV on hepatitis C Enhanced HCV replication Decreased response rates to HCV treatment Faster progression of fibrosis, leading to the earlierappearance of end-stage liver disease More severe inflammation HIV treatment (ART) slows down the progressionof liver disease NEGATIVE IMPACT ON HCV PATHOGENESIS
  15. 15. Kim & Chung, Gastroenterology 2009;137:795
  16. 16. Effects of HIV-gp120 on hepatic stellate cells HSC migration Cytokine expression Bruno, Galastri et al., Gut 2010
  17. 17. HSC recruitment HIV-infected cells via migration gp120-expressing virions MCP-1(CCL2) secretionFurther recruitment of fibrogenic and inflammatory cells.
  18. 18. All Roads lead toFibros Rome! is ASH AIH NASH HCV Iron HIV Vascularcoinfection HBV Biliary
  19. 19. Why fat?1. Severe obesity is associated with a greater prevalence of NAFLD, NASH, and cirrhosis2. Alcoholic steatohepatitis is more severe in the presence of obesity3. Steatosis accelerates disease progression in chronic hepatitis C and other chronic liver diseases4. The response to antiviral therapy in HCV patients is lower in the presence of fatty liver
  20. 20. Adipose tissue changes after weight gain ↑FFA Adipose tissue IR Lipolysis TNF-α TNF-α ↑ Leptin ↑ Leptin IL-1β IL-1β ↓ Adiponectin CCL2 ↓ Adiponectin CCL2 OPN OPN Treg iNOS iNOS ↑M1 CCL2 CCL2 Weight Weight gain gain M1 Apoptosis M2 ↓M2 ↓Treg Hypoxia Marra & Lotersztajn, Curr Pharm Des 2012; in revision
  21. 21. Inflammation ADIPOKINES: cytokines of the Resistin (humans) Tumor necrosis factor Adipose tissue IL-6 IL-1 IL-10 IL-1 receptor antagonist Monocyte chemoattractant protein-1 (CCL2) RANTES (CCL5) IL-8 (CXCL8) Metabolic control Interferon.inducible protein-10 (CXCL10) Leptin Migration inhibitory factor (MIF) Adiponectin Hepcidin Resistin (rodents) Adipsin Visfatin Serum amyloid protein A Retinol binding protein 4 Apelin Vaspin Omentin Tissue repair Chemerin Angiotensinogen Renin Acylation stimulating protein Plasminogen-activator inhibitor-1 (PAI-1) Agouti signaling protein 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 factorMarra & Bertolani, Hepatology 2009;50:957
  22. 22. ResistinAdiponectin Leptin
  23. 23. Leptin Deposition of fibrillarProliferation/survival matrix Jak-2 ERK-1/2 PI3K/Akt Phagocytosis of ROS Inhibition of matrix apoptotic bodies degradation Cell migration Chemokine secretion ADIPONECTIN NADPH oxidase Angiogenesis activation Modified from Bertolani & Marra Curr Pharm Des 2010;16:1929
  24. 24. Abu-Shanab & Quigley, Nat RevGastroenterol Hepatol.2010; 7;691
  25. 25. Inflammasome deficiency worsens NASH interacting with the microbiome Innate immune deficiency  Altered microbiota  Activation of TLR4 & TLR9  Proinflammatory signals  Transmissible by co-housing NAFLD Based on: Henao-Mejia et al., Nature 2012; 482:179
  26. 26. Gut Excess free LPS fatty acids Bacterial Toxic lipids TLR4 DNA TLR9 IL1, danger signals ROS Activated Kupffer cells Chemokines Cytokines (CCL2) (TNF, IL1) Hepatocyte Hepatocyte steatosis injury Monocyte- derived macrophage Inflammatory cell Inflammatory cell recruitment Cytoki Cytokirecruitment recruitment nes nesChemokines Hepatic stellate cells Fibrogenesis Marra & Lotersztajn, Curr Pharm Des 2012; in revision
  27. 27. The ‘multiple parallel hits’ hypothesis Tilg & Moschen, Hepatology 2010;52:1836
  28. 28. Genetic predisposition to fibrosis
  29. 29. Zimmer & Lammert, Best Pract Res Clin Gatsroenterol 2011
  30. 30. Zimmer & Lammert, Best Pract Res Clin Gatsroenterol 2011
  31. 31. Adiponutrin (PNPLA3) genotype is associated with the severity of damage and fibrosis NASH Fibrosis Valenti et al., Hepatology 2010;51:1209
  32. 32. GWAS of susceptibility to fibrosis in HepC Several susceptibility loci for HCV-induced liver fibrosis, linked to genes that regulate apoptosis. Patin et al., Gastroenterology 2012
  33. 33. Paternal epigenetic suppression of hepatic fibrosis in male progeny Zeybel et al., Nat Med 2012
  34. 34. Paternal epigenetic suppression of hepatic fibrosis in male progeny SL Friedman, Nat Med 2012
  35. 35. Pathways in fibrosis that promote HCC Zhang & Friedman, Hepatology 2012
  36. 36. How can we measure fibrosis in clinical practice?
  37. 37. Progression of chronic liver diseases F0 F1 F2 F3 F4 Numerous Numerous FibrosisNo fibrosis Few septa Septa W/O Septa WITH without septa cirrhosis CIRRHOSISDeranged microvascular anatomy Portal hypertension Cancer
  38. 38. Notes from EASL clinical practice guidelines Assessment of the severity of hepatic fibrosis isimportant in decision making in chronic hepatitis Ctreatment and prognosis Liver biopsy is still regarded as the referencemethod to assess the grade of inflammation and thestage of fibrosis Serological markers and transient elastography […]have a performance, when used alone or together,[which] has been reported to be comparable with liverbiopsy
  39. 39. Chronic liver diseases:Methods to establish disease progression Imaging: US, CT, MRI Serum Markers Stiffness HVPGLiver Biopsy: 1:50,000 of liver tissue
  40. 40. Serum markers
  41. 41. Gressner et al., World J Gastroenterol 2009; 28:2433
  42. 42. Currently available serum markers Indirect markers Direct markers Combination markers
  43. 43. Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
  44. 44. Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
  45. 45. 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:  Selection of patients to be biopsied 
  46. 46. Algorithms?
  47. 47. SAFE biopsy for significant fibrosis (> F2) Castera et al., J Hepatol 2010;52:191
  48. 48. The Castera algorithm for significant fibrosis Castera et al., J Hepatol 2010;52:191
  49. 49. Genes instead of biochemical markers?
  50. 50. A 7 gene signature identifies the risk ofdeveloping cirrhosis during chronic hepatitis C Huang et al., Hepatology 2007;46:297
  51. 51. Marcolongo et al., Hepatology 2009
  52. 52. Transient elastography
  53. 53. 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 Not reliable with obesity or ascites
  54. 54. AUCGRAY AREA
  55. 55. Multilevel likelihood ratios for the prediction of significant fibrosis, and cirrhosisLikelihood ratios above 10 and below 0.1 provide strong evidence to rule inor rule out diagnoses, respectively. Arena et al., Gut 2008;57;1288
  56. 56. Suspected Fibrogenic Liver Disease Transient elastography ≤6 kPa Intermediate values ≥12 kPa No significant Advanced fibrosis or Gray area fibrosis cirrhosis F0 F1 F2 F3 F4 No biopsy Biopsy if results No biopsy influence management Treat and/or Possible implementation screen forFollow-up varices and HCC with other NIT Modified from Vizzutti et al., Gut 2009;58:157
  57. 57. Poor classification of intermediate stages by non-invasive tests Cales et al., Liver Int 2008;28:1352
  58. 58. L. Castera, Gastroenterology 2012
  59. 59. In search for a better standard
  60. 60. Inaccuracy of biopsy affects marker perfomance When errors in the diagnostic test and the gold standard are independent, the observed sensitivity and specificity of the diagnostic test will be underestimated Mehta et al., J Hepatol 2009;50:36
  61. 61. ELF test can predict clinical outcomes Parkes et al., Gut 2010;59:1245
  62. 62. Parkes et al., Gut 2010;59:1245
  63. 63. Vergniol et al., Gastroenterology 2011;140:1970
  64. 64. Predicting clinical outcomes with standard laboratory tests in chronic hepatitis C Ghany et al., Gastroenterology 2010;138:136
  65. 65. Ghany et al., Gastroenterology 2010;138:136
  66. 66. What we would like to have from a non- invasive tool1. Diagnostic accuracy >0.8 for advanced fibrosis2. Diagnostic accuracy >0.9 for cirrhosis3. Ability to detect major changes in fibrosis (e.g. >2 METAVIR stages)4. Correlate with long-term clinical outcomes5. Applicability across different types of liver diseases6. Known profile in control subjects7. Possibility to be combined with other staging modalities to build an algorithm
  67. 67. Fibrosis Vs. Fibrogenesis Chronic HCV-Hepatitis Collagen I HAI Score: 11 METAVIR: F1PDGF PDGF-R β
  68. 68. The need for a ‘dynamic’ serum marker to assess fibrosis in clinical practice1. Not for cross-sectional staging or diagnosis2. Sensitive to rapid changes in fibrogenesis and/or fibrolysis3. Possibly related to ECM turnover4. Specific for a given chronic liver disease
  69. 69. Role of biopsy in the management of chronic hepatitis C Contribution to staging in selected cases Grading Assessment of associated lesions (e.g.NAFLD) Additional information in the presence ofdiscrepant non-invasive tests Masurement of collagen proportionate area
  70. 70. Liver Biopsy1. - Provides clues about etiology2. - Provides clues about cofactors3. - Allows immunohistochemical, biochemical and biomolecular investigations4. - Allows assessment of iron content5. - Allows grading (activity) and staging (fibrosis): gold standard?
  71. 71. Histological-hemodynamic correlations in cirrhosis Septal thickness Nodule size Nagula et al., J Hepatol 2006; 44:111
  72. 72. Morphometric analysis of advanced fibrosis “In advanced chronic hepatitis C, fibrosis increases at a rapid pace that can only be detected by morphometry” Goodman et al., Hepatology 2007;45:886
  73. 73. Collagen area better correlates with HVPG than Ishak stage Predictor of HVPG > 6 mm Hg Ishak grading score 0.138 Ishak staging score 0.067 Collagen proportionate area <0.001 Predictor of HVPG > 10 mm Hg Ishak grading score 0.477 Ishak staging score 0.05 Collagen proportionate area 0.009 Calvaruso, Burroughs et al., Hepatology 2009;49:1236
  74. 74. Schuppan & Afdhal, Lancet 2008;371:838
  75. 75. Biopsy Patient Biopsy categorization Clinical Clinical evaluation evaluation Follow-up with Follow-up with noninvasive noninvasive markers markers Imaging ImagingSerum markersSerum markers Unstable Stable Fibroscan Fibroscan Repeat biopsy Repeat biopsy
  76. 76. Present and future of HCV infection F0 Decompensation F1 F4 F2 F3 HCC Davis et al., Gastroenterology 2010;138:513
  77. 77. Classification of chronic liver disease Garcia-Tsao et al., Hepatology 2010
  78. 78. Progression of CLD: Key Pathophysiological Points Systemic Disease Parenchymal Failure Portal Hypertension, Carcinogenesis Tissue Hypoxia, Angiogenesis Chronic Tissue Damage, Inflammation, FibrogenesisFrom Chronic Damage to Decompensated Pre-Cirrhosis Compensated Cirrhosis Significant Fibrosis Cirrhosis
  79. 79. Assessment of fibrosis progression and regression in different disease stages HVPG Stage at liver biopsy Biopsy (TJLB?) + morphometry Liver stiffness Liver stiffness Biochemical markers Biochemical markers? COMPENSATED CIRRHOSISF0 F1 F2 F3 F4 or HVPG < 10 mmHg HVPG > 5 mmHg
  80. 80. Splenic elasticity is a marker of portal Hypertension Hirooka et al., Radiology 2011
  81. 81. Progression of hepatitis C: clinical needs for patient managementBeginning ofinfection Predict and Monitor rate of Fibrosis Regressiondifficult toassess Detect early Detect significant fibrosis Monitor the anatomical predictors of Predict rate of progression: worsening beyond F4 decompensation From Chronic Damage to Decompensated Pre-Cirrhosis Compensated Cirrhosis Significant Fibrosis Cirrhosis Distinguish Advanced Fibrosis Predict the occurrence from Cirrhosis of HCC
  82. 82. Towards a new classification of cirrhosis Arvaniti et al., Gastroenterology 2010;139:1246
  83. 83. Does increased knowledge of pathogenesis translate into antifibrotic therapies?
  84. 84. Virus, Ethanol, Iron, Treat the primary disease: Autoimmunity, Interferon/RibavirinFat, Biliary damage Nucleos(t)ide analogs Abstinence Venesection Immunosuppression Weight loss & physical activity Biliary decompression Damage
  85. 85. Inflammation Corticosteroids Chemokine antagonists Oxidative stressVirus, Ethanol, Iron, Antioxidants Autoimmunity, Herbal medicines (curcumin)Fat, Biliary damage Apoptosis UDCA Caspase inhibitors Hepatic Growth Factor (HGF) Cytokine secretion Pentoxifylline Decoy receptors Damage MAb
  86. 86. Targeting hepatic stellate cell activation Interferon-γ PPAR-γ agonists Imatinib (PDGF) Bosentan (ET-1) NO-donors CB-1antagonists ACE-I/ARB Modified from Marra et al., Semin Immunopathol 2009; e-pub Jun 17
  87. 87. Limitation of matrix deposition Anti-TGF-β ColchicineApoptosis of activated stellate cells Promote matrix degradationSulfasalazine HalofuginoneGliotoxin MMP over-expression
  88. 88. Antifibrotic drugs already in clinical use Colchicine Pentoxifylline Canrenone Statins COX inhibitors N-acetyl-L-cysteine (NAC) NO donors Thiazolidinediones Angiotenin receptor blockers
  89. 89. Molecular plausibility In vitro actions Effects in in vivo models Safety/tolerability Clinical trials of an antifibrogenic drug Use in clinical practice Translational research and the development
  90. 90. Problems with trials of antifibrotic drugsClinical benefit requires a long period of time‘Competition’ with antiviral agentsRequirement for liver biopsyEfficacy may not be assessed by a simple testDifficulties in measuring the endpointIdentification of patients more likely to respond
  91. 91. Lessons from antifibrotic trials Clinical benefits require a long period of time Need for noninvasive markers Quantitative analysis of biopsies to assessfibrogenesis Possible interference with viral replication Biomarker identification for personalizedtherapy
  92. 92. Selection of patients for antifibrotic trialsEtiology:HCV or HBV: known natural historyNASH: several components for prognosisAlcohol: dependance of abstinenceBiliaryFibrosis stage:Avoid advanced cirrhosisConsider gradingRate of fibrosis progression:Stratification
  93. 93. Progression of autoimmune hepatitis Hudacko & Thiese Arch Pathol Lab Med 2011
  94. 94. Changes in fibrillar matrix affects degradation EARLY FIBROSIS MMPs COLLAGEN CROSS-LINKING PRESENCE OF ELASTIN ACELLULAR FIBROSISESTABLISHED FIBROSIS
  95. 95. Deranged microvascular anatomy in cirrhosis Extensive FIBROSIS and conversionNormal liver of normal liver architecture into Cirrhotic liver STRUCTURALLY ABNORMAL NODULES Establishment of INTRAHEPATIC VASCULAR SHUNTS between afferent B and efferent vessels of the liver Onori et al., J Hepatol 2000; 33:555
  96. 96. Which is the best drug to test?1. Easily administered2. Tolerable for a long time3. Safe and devoid of off-target effects4. Potency might not be the real issue
  97. 97. Angiotensin receptor signaling predicts the response to losartan ATII-Racytoplasm IKKγ (NEMO) IKK1 IKK2 P IκB p50 p65 Pnucleusmodified from Marra, Gut 2008;57:570 Oakley et al., Gastroenterology 2009;136:2334
  98. 98. Diagnostic endpoints Biopsy: scored the right way and assessingfibrogenesis (e.g. alpha-SMA) Serum tests Elastography Imaging Portal pressure (advanced fibrosis or earlycirrhosis)
  99. 99. Perspectives for antifibrotic therapies Cell-based therapies Gut microbiota/TLRs Angiogenesis Weight loss Herbal medicine
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