Evolution of Liver Fibrosis in Chronic Hepatitis B Dr. Loey Lung-Yi Mak MBBS (HKU), MRCP (UK), PDipID (HKU) Division of Gastroenterology & Hepatology Department of Medicine Queen Mary Hospital Queen Mary Hospital
Outline • Pathogenesis of liver fibrosis in CHB • Assessment of liver fibrosis in CHB • Concept of fibrosis progression • Concept of fibrosis regression
Outline • Pathogenesis of liver fibrosis in CHB • Assessment of liver fibrosis in CHB • Concept of fibrosis progression • Concept of fibrosis regression
Chronic hepatitis B disease phases Yuen MF et al. Nat Rev Dis Primers 2018
Chronic hepatitis B disease progression HCC 5-15% Liver Liver Acute Chronic LT Death Cirrhosis infection infection fibrosis fibrosis ~30% >90% vertical transmission <5% immunocompetent adults Liver failure Lok ASF. New Eng J Med 2002 McMahon BJ. Hepatology 2009 HCC: hepatocellular carcinoma McMahon BJ. Clin Liver Dis 2010 LT: liver transplantation
Liver fibrosis – pathogenesis • Liver fibrosis = wound healing in response to liver damage with excessive ECM molecules deposition • Component of extra-cellular matrix (ECM) molecules – Fibril forming interstitial collagens (type I, III) – Basement membrane collagen type IV – Non-collagenous glycoproteins (e.g. fibronectin, laminin, tenascin, M2BPGi) – Proteoglycans (e.g. heparan, hyaluronic acid) Schuppan D et al. Sem Liver Dis 2001 Bedossa P et al. J Pathol 2003 Schuppan D et al. Lancet 2008 K Shirabe et al. J Gastroenterolol 2018
TIMP Activated HSC Figure adapted from Friedman SL. J Biol Chem 2000
Excessive ECM molecules deposition: Portal tract Peri-portal (septal) Portal-portal bridging Cirrhosis Figure adapted from Batts KP et al. Am J Surg Pathol 1995
Outline • Pathogenesis of liver fibrosis in CHB • Assessment of liver fibrosis in CHB • Concept of fibrosis progression • Concept of fibrosis regression
Liver Biopsy: Scoring Systems for Histologic Stage Ishak METAVIR Appearance Ishak Description Score 1 Score 2 No fibrosis 0 F0 Fibrous expansion of some portal areas ± short fibrous 1 F1 septa Fibrous expansion of most portal areas ± short fibrous 2 septa F2 Fibrous expansion of most portal areas with occasional 3 portal to portal (P–P) bridging Fibrous expansion of most portal areas with marked 4 bridging (P–P and portal to central [P–C]) F3 Marked bridging (P–P and/or P–C) with occasional nodules 5 (incomplete cirrhosis) Cirrhosis 6 F4 1. Bedossa P, Poynard T. Hepatology . 1996;24:289-293; 2. Ishak K, et al. J Hepatol . 1995;22:696-699. Figure adapted from Standish RA, et al. Gut . 2006;55:569-578.
Liver biopsy: out of favour in clinics Sampling error Inter- & intra- observer (1 in 50,000) – length variability (up to 33% & degree of discrepancy) fragmentation Risks and Categorical mortality scoring Liver (1:10,000) systems biopsy Regev A et al. Am J Gastroenterol 2002
Methods of assessing liver fibrosis 1. Liver biopsy 2. Serum biomarkers 3. Imaging-based techniques EASL-ALEH. J Hepatology 2002
Parikh P et al. Ann Transl Med 2017
Transient Elastography Visco-elastic characteristic of liver tissue • AUROC of 0.88 for significant fibrosis & • 0.96 for cirrhosis with >80% sensitivity and specificity in CHB Confounded by ALT, cholestasis, • congestive heart failure etc. EASL-ALEH. J Hepatology 2015
Outline • Pathogenesis of liver fibrosis in CHB • Assessment of liver fibrosis in CHB • Concept of fibrosis progression • Concept of fibrosis regression
Fibrosis progression in CHB Histology Transient elastography
Factors associated with fibrosis progression in CHB HBV (N=610) • Viral – HBV DNA – HBeAg/ anti-HBe – Genotypes – Core promoter mutation • Host – Age – Gender – Liver biochemistry – Metabolic syndrome – Baseline liver fibrosis stage – Alcohol Ikeda K et al. J Hepatol 1998 Yuen MF et al. Am J Gastro 2004 Yuen MF et al. J Viral Hepat 2005
Liver fibrosis progression in HBeAg + treatment-naïve patients N=426 Treatment naïve Interval of 42 months, 13 patients (5.2%) developed liver fibrosis progression • 74 immune-tolerant: 4.1% • 137 immune-reactive: 6.6% p=0.45 Wong GL et al. J Gastroenterol Hepatol 2013
Fibrosis progression in treatment-naïve patients with metabolic syndrome N=663, treatment naïve, E+ or E- interval of 44 months 107 (16%) patients developed liver fibrosis progression • No. of metabolic risk factors • Most obvious in the immune-tolerant phase Wong GL et al. Aliment Pharmacol Ther 2014
Fibrosis progression in HBeAg-ve patients after 10 years (N=459) Fibrosis progression in 10.7% treatment-naïve patients • (N=224) In 6.8% treatment-experienced • patients (N=235) All patients: Treatment with NA (OR 0.436, 95% CI 0.192 – 0.990, p = 0.047) TN: TE: Metabolic syndrome CAP score (OR 4.595, 95% CI: 1.072 – 19.701, (OR 1.017, 95% CI: 1.006 – 1.029, Mak LY et al. Manuscript submitted p = 0.040) p = 0.003)
Fibrosis regression in CHB Histology Transient elastography Serum markers
Liver fibrosis is a dynamic process • Conditions to satisfy for fibrosis regression : – the inciting agent is removed – sufficient time is allowed for the return to normal liver structure fibrogenesis fibrinolysis
Fibrinolysis by MMP, macrophages and Kupffer cells Apoptosis/ return to quiescent stage for activated HSCs Figure adapted from Friedman SL. J Biol Chem 2000
Fibrosis regression following antiviral therapy
Achievements of the Present Antiviral Treatment Mortality reduction Transplant need reduction Clinical Outcomes HCC reduction Cirrhosis reduction Histological response Fibrosis regression Serological response HBsAg seroclearance Histological response Histological improvement Serological HBeAg loss-seroconversion response Virological HBV DNA negativity response Biochemical ALT normalisation response Short-term goal Medium-term goal Long-term goal Treatment start Su TH & JH Kao Expert Rev Gastroenterol Hepatol 2015;9(2):141-54
Long-term ETV lead to reduction of Ishak fibrosis score (N=57) Long-term = 6 (range, 3-7) years of ETV All 10 patients out of 57 with F3/4 (Ishak >= 4) at baseline had at least 1 point reduction of Ishak score (median reduction 1.5) Chang TT et al. Hepatology 2010
Long-term TDF lead to reduction of Ishak fibrosis score (N=348) 176 (51%) had fibrosis regression at week 240. Of 96 (28%) with cirrhosis at baseline, 71 (74%) no longer had cirrhosis. Marcellin P et al. Lancet 2013
Use of antiviral therapy led to progressive reduction in LS Antiviral therapy Interval of 512 days 12.9 kPa à 6.6 kPa (P = 0.0001) No antiviral therapy Interval of 422 days 6.1 kPa à 6.3 kPa (P = 0.0682) Osakabe K et al. J Gastroenterol 2011.
Systematic review with meta-analysis Facciorusso A et al. Dig Liver Dis 2018
N=459, all HBeAg – ve Proportion of patients in F4 reduced from 16% to 6% after 10-year interval (P <0.001) Mak LY et al. Manuscript submitted
Histological (Ishak) fibrosis stage improvement and reduction in serum fibrosis marker (M2BPGi) after NA therapy N=145 N=54 Mak LY et al. Clin Tranl Gastroenterol 2018
Fibrosis regression following HBsAg seroclearance Histology Transient elastography
Low fibrosis stage after HBsAg seroclearance on liver biopsy • N=26 Age at the time of liver biopsy: 40.5 years • Duration after HBsAg seroclearance: 47.8 months • 17 (65.4%) patients had no evidence of necroinflammation and fibrosis • The remaining 9 (34.6%) patients had inflammation and/or fibrosis • Yuen MF et al. Gastroenterology 2008
Reduction in liver fibrosis score after HBsAg seroclearance (N=11) Mean duration of HBsAg seroclearance: 3.9 years Fong TL et al. Hepatology 1993
Lower liver stiffness after HBsAg seroclearance only if persistent normal ALT N=95 Across 3 years ALT categories: 1: normal ALT at 1 st LSM, high ALT at 2 nd LSM 2: high ALT at 1 st LSM, normal ALT at 2 nd LSM 3: normal ALT at both LSM 4: high ALT at both LSM Fung J et al. J Viral Hepat 2011
Liver stiffness declined progressively with increasing duration of HBsAg seroclearance (N=45) r = - 0.5 ( P <0.001) Mak LY et al. Manuscript submitted
Early HBsAg seroclearance < 50 was associated with lower risk of significant fibrosis & HCC Age of HBsAg-Seroclearance % of Significant fibrosis (LS >8.1 kPa) P value < 50 years (N=76) 6 (7.9%) 0.001 ≥ 50 years (N=78) 23 (29.5%) Yuen MF et al. Gastroenterology 2008
Chronic hepatitis B disease progression Antiviral therapy HCC HBsAg seroclearance 5-15% Liver Liver Acute Chronic LT Death Cirrhosis infection infection fibrosis fibrosis ~30% >90% vertical transmission <5% immunocompetent adults Liver failure Lok ASF. New Eng J Med 2002 McMahon BJ. Hepatology 2009 HCC: hepatocellular carcinoma McMahon BJ. Clin Liver Dis 2010 LT: liver transplantation
Conclusion • Fibrosis progression is heightened by ongoing virological activity and metabolic factors • Fibrosis (and even cirrhosis) regression is possible by minimizing liver injury and allowing time for recovery – Antiviral therapy – HBsAg seroclearance • Evidence of benefits of fibrosis regression in terms of clinical outcomes – Lower HCC risk
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