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Liver fibrosis

hepatic fibrosis basics to ongoing trials

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HEPATIC FIBROSIS
Dr Srujan kumar
PGY 1 Gastro enterology
Gandhi Hospital
HEPATIC FIBROSIS
DEFN: Reversible wound healing response
characterised by accumulation of extracellular
matrix/scar
follows chronic, but not selflimited
liverdisease.
Natural history
Rapid fibrosers and slow fibrosers:
variable progression of fibrosis was first
highlighted in patients with Hepatitis C
Study emphasized the influence of both
modifiable and non modifiable factors
Liver fibrosis
Liver fibrosis
Liver fibrosis
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Liver fibrosis

  • 1. HEPATIC FIBROSIS Dr Srujan kumar PGY 1 Gastro enterology Gandhi Hospital
  • 2. HEPATIC FIBROSIS DEFN: Reversible wound healing response characterised by accumulation of extracellular matrix/scar follows chronic, but not selflimited liverdisease.
  • 3. Natural history Rapid fibrosers and slow fibrosers: variable progression of fibrosis was first highlighted in patients with Hepatitis C Study emphasized the influence of both modifiable and non modifiable factors
  • 8. Cellular and molecular features Between the sinusoid and hepatocytes fenestrated endothelial cells line a basement membrane which seperates the sinusoidal lumen from space of Disse Nutrients and other molecules reach the basal surface of hepatocyte by passing through the fenestrae of sinusoidal wall and across space of Disse- This process is impaired by cellular and matrix changes in liver injury
  • 10. Cellular and molecular features ECM COMPOSITION: Normal and scar tissue Normal liver has connective tissue matrix which includes type 4 /nonfibrillary collagen Glycoproteins(fibronectin,laminin) and proteoglycans(Heparan sulphate)
  • 11. After Hepatic injury there is 3 to 8 fold increase in ECM composed predominantly of high density interstitial fibril forming collagens types 1 and 3 rather than type4 as well as cellular fibronectin,hyaluronic acid and other matrix proteoglycans and glycoconjugates Gradual accumulation of type 1 collagen results from inceased synthesis and reduced degradation :Hallmark of fibrogenesis
  • 12. Stellate cell Activation: A central feature Hepatic stellate cell/ HSC is the principal cell involved in fibrogenesis In the normal liver these HSC have intracellular droplets containing vit.A .They contain 40-70%of body stores of retinoids In it’s quiscent stage the HSC produces predominantly type4 collagen- characteristic of normal basement membrane Activation : refers to phenotypic changes occuring in HSC with injury
  • 13. Phenotypic changes in HSC in Activation stage • Loss of retinoid droplets • Cellular proliferation • Increased endoplasmic reticulum • Increased contractility with expression of smooth muscle specific a-Actin and secretion of cytokines and chemokines This phenotypic switch is also characterized by production of type 1 collagen, the high density interstitial collagen characteristic of cirrhotic liver as well as matrix degrading enzymes
  • 15. Stellate cell activation occurs in two stages : INITIATION PERPETUATION Initiation refers to early events including rapid changes in gene epression and a cellular phenotype that renders HSCs responsive to cytokines and other stimuli Perpetuation involves cellular events that amplify the activated phenotype through enhanced cytokine expression and responsivess and acquisition of features critical to development of fibrosis
  • 19. Diagnosis and Assesment • Accurate assesment of fibrosis is essential to guide management and predict prognosis in patients with chronic liver disease 1)Invasive (Histology of liver biopsy)- Gold std for quantifying fibrosis 2)Non invasive : serology and Radiology tests
  • 20. Three methods of staging in widest use are: The Ishak score Metavir score Desmet/scheur staging system
  • 26. Non invasive assesment Direct markers : reflect ECM turnover procollagen type 1carboxy terminal peptide(picp): increased in cirrhosis.not accurate in ALD,HCV Procollagen type 3(PIIINP) : serum levels corelate with histologic stage of inflmmation,fibrosis in ALD,VIRAL HEPATITIS,PBC TYPE 1 ANDTYPE 4 COLLAGEN : increaed in all types of fibrosis. Levels of type 1 corelated wih fibrosis score
  • 27. Laminin : serum levels increase with peri sinusoidal fibrosis co relate with severity of fibrosis,hepatitis,CTP ,HVPG Hyaluronic acid:Have greatest predictive accuracy for advanced fibrosis YKL 40/CHONDREX: 38KD Glycoprotein with function in remodelling and degradation of ECM.Levels corelate with degree of fibrosis Matrix metalloproteinase/mmp 2,3,9: only MMP 2 corelate with degree of fibrosis TIMP 1&2 : 100 %sensitivity for diagnosis in cirrhosis but low specificity CYTOKINES AND CHEMOKINES : TGF ALPHA,BETA,PDGF Levels corelate with severity of liver dysfunction
  • 28. Panels of direct markers of fibrosis Direct markers have been combined into panels to predict fibrosis.The panels may also include indirect markers FIBROSPECT II :serum hyaluronic acid,TIMP alpha 2macroglobulin sn 77% sp73% in a study of 402pts with HCV SHASTA : serum hyaluronic acid,serum AST Albumin level Evaluated in pts with hiv/hcv co infection Cutoff value <0.30(sn 88%, npv>94%) for significant fibrosis
  • 29. Indirect markers Reflect alteration in hepatic function AST to PLATELET RATIO INDEX(APRI): meta analysis of 40 studies found that for predicting significant fibrosis(F2 to F4) ,APRI cutoff of 0.7 had sensitivity of 77% and sp 72% APRI appears most useful for excluding significant fibrosis in HCV
  • 30. Fibotest/fibrosure and Actitest Fibrotest : alpha2 macroglobulin,alpha2 globulin(haptoglobin),gamma globulin,apolipoprotein A1,GGT and Total bilirubin Sensitivity for detection of significant fibrosis is 60to 75% and sp 80-90% Actitest is a modification of above that incorporates ALT and reflects both fibrosis and necroinflammatory activity Metanalysis including 1570pts concluded that these tests were reliable alternatives to Liver biopsy in pts with chronic HCV
  • 31. HEPA SCORE:Bi ,GGT,Hyaluronic acid,Alpha2 macroglobulin,Age ,Sex AST/ALT ratio: more than 1 suggests cirrhosis utility is uncertain due to inconsistent results
  • 32. Other indirect markers • FIB 4 INDEX: combines biochemical values(Plt count,ALT and AST) and age. useful in pts with HCV,NAFLD Values have been associated with risk of development of HCC in those who consume alcohol(>1.75) NAFLD FIBROSIS SCORE: Age,BMI,Blood glucose,Aminotransferase levels,PLT count,Albumin sn 43%,sp96% for advanced fibrosis(F3 to F4) PGA INDEX: PT index,GGT,Apolipoprotein A1 Validated in pts of ALD Accuracy for detection of cirrhosis is 66to 72%
  • 33. • Fibro index(plt count,AST,gammaglobulin) accuracy is still being determined • FORNS INDEX(age,GGT,cholesterol,plt) performance characteristics similar to those seen with APRI • FIBROMETER: Plt count,PT index,AST, Alpha2macro globulin hyaluronic acid,BUN,age performed well in predicting severe fibrosis in chronic viral hepatitis
  • 34. • BARD score: Developed to predict fibrosis in NAFLD BMI, AST/ALT, DM Sudies showed ppv and Npv of 69 and 96% for advanced fibrosis
  • 35. Radiologic tests Radiologic methods are emerging as promising tools USG based elastography( most studied radiologic test) Magnetic resonance elastography(MRE) Acoustic radiation force impulse imaging(ARFI) Cross sectional imaging
  • 39. MR Elastography • Detecting any fibrosis (F1): cutoff 3.45kpa • Detecting significant fibrosis(F2): cutoff 3.66kpa • Detecing advanced fibrosis(F3)optimal cutoff 4.11kpa • Cirrhosis(F4): optimal cutoff 4.71kpa Higher technical success and diagnostic accuracy compared to US elastography Advantage of scanning entire liverand thus doesnot depend on acoustic window May also detect lesions with in liver .eg: HCC
  • 40. Acoustic radiation force impulse imaging (ARFI) Another USG based approach for estimating liver stiffness Uses short duration high inensity acoustic pulses to produce mechanical excitation in tissue.This results in localized displacement and shear wave propogation Velocity of these waves corelate with degree of fibrosis Cutoff values: 1.44m/s ( F2 ) 1.9m/s (F4)
  • 46. Inhibition of Hepatic Injury • PAN-CASPASE INHIBITOR: IDN-6556 attenuated hepatic injury and fibrosis in mice • OCADEIC ACID protects in part from liver fibrosis by protecting hepatocytes from injury • ANTI OXIDANTS: regulating ROS is a promising strategy of liver fibrosis therapy • PPARδ agonist protects hepatocytes from cell death by reducing ROS generation of hepatocytes, leading to less liver fibrosis
  • 47. Nuclear Receptors • PPAR𝛾 and Farnesoid X receptor (FXR), that play an important role in HSC regulation • PPAR𝛾 ligands/agonists, PPAR𝛾 expression is restored, and HSC activation and collagen expression are reduced in vitro • obeticholic acid, semisynthetic FXRagonist, showed improvement of the histological and biochemical markers, ameliorated fibrosis, inflammation, and steatosis in NASH patients • Obeticholic acid :clinical trials for long-term treatment of cholestatic liver diseases
  • 50. Inhibition of Inflammation • Serum amyloid P (SAP) or pentraxin-2, a member of the pentraxin family, is a 27-kDa protein that is produced by the liver, secreted into the blood, and circulates as stable 135-kDa pentamers . • SAP reduces 1. neutrophil adhesion to ECM proteins 2. inhibits the differentiation of monocytes into fibrocytes 3. decreases profibrotic macrophages 4. activates the complement pathway 5. promotes phagocytosis of cell debris. • SAP reduces bleomycin-induced lung fibrosis . • Injection of SAP into humans, mice and rats has no toxic effects.
  • 51. Inhibition of Activation of HSCs • Fresolimumab (GC1008) is a human anti-TGF- β1 monoclonal antibody that neutralizes all isoforms of TGF-β • TGF-β transduces its signal to target genes through the ALK5 Ser/Thr kinase receptor. GW6604 , an ALK5 inhibitor, inhibits the transcription and deposition of ECM and improves the deterioration of liver function in mice
  • 52. • Integrin αvβ1 expressed on activated HSCs. Inhibitor of αvβ1 prevents TGF-β1 activation and inhibits experimental liver fibrosis • Lysophosphatidic acid (LPA) is a lipid mediator, which is produced mainly by activated platelets. LPA1R antagonists showed anti- fibrotic effect on models of liver fibrosis
  • 54. Inhibition of Proliferation of HSCs • Inhibitors of receptor tyrosine kinase and Ser/Thr kinase also demonstrate anti-fibrosis effects • tyrosine kinase inhibitor sorafenib :HCC, and sunitinib can improve experimental hepatic fibrosis, inflammation, and angiogenesis • SiRNA melastatin 7, a nonselective cation channel with protein serine/ threonine kinase activity, attenuates TGF-β1-induced expression of myofibroblast markers, increases the ratio of MMPs/TIMPs, and decreases the phosphorylation of Smad2 and 3 associated collagen production
  • 55. • Hepatic nuclear factor kappa B inducing kinase, a Ser/Thr kinase – target for liver fibrosis therapy • RAS pathway in HSCs induces ROS and accelerates hepatic fibrosis , accelerates inflammation, tissue repair and fibrogenesis by production of angiotensin II • HALT-C cohort study did not show any antifibrogenic effects of ACEi/ARB for chronic hepatitis C patients • Activation and proliferation of HSCs require NOX/ ROS signaling.
  • 59. NOX • HSCs express 3 NOX isoforms, NOX1, NOX2, and NOX4. • NOX2 :phagocytic cells use to produce ROS to kill bacteria, not a good target for anti-fibrotic therapy. • HSCs from p47 phox -deficient mice (without a regulatory component of NOX) fail to generate ROS in response to Ang II, PDGF, leptin, or apoptotic bodies, and p47 phox - deficient mice demonstrate reduced liver fibrosis after BDL or the hepatotoxin CCl4 . • NOX1 and NOX4 are expressed as activated HSCs, but only at very low levels in the uninjured liver. • GKT137831, a potent dual NOX1/ NOX4 inhibitor, attenuates ROS production and inhibits activation of HSCs and experimental liver fibrosis
  • 61. Promotion of Apoptosis of Activated HSCs • CB1 and CB2 receptors are increased in liver fibrosis. • CB1 agonists activate HSCs to myofibroblasts. • CB1 receptor agonists, Rimonabant, inhibit and reverse experimental liver fibrosis. • MMP: Monoclonal Anti-TIMP1 Ab partially reverses established CCl4-induced fibrosis • a decrease in TIMP-1 protein levels correlated with decreased numbers of HSCs
  • 62. Promotion of HSC Inactivation • Inactivation of HSCs is associated with the re- expression of lipogenic genes PPAR-γ, Insig1, and CREBP. • PPAR-γ is reported to be important for maintaining and for re-establishing the quiescent phenotype
  • 63. Inhibition of Deposition of Type I Collagen • In liver fibrosis, ↑ type I collagen . cross-linking of type I collagen is also increased , enzyme lysyloxidase-like-2 (LOXL2). • inhibition of LOXL2 by a monoclonal antibody (AB0023) reduces the production of cytokines, attenuates TGF-β signaling, and inhibits the activate fibroblasts (Barry-Hamilton, 2010). • Similar to AB0023, another humanized monoclonal LOXL2 antibody (GS-6624) is in randomized, double blind, phase II clinical trials to treat NASH and PSC