Evolution of Liver Fibrosis in Chronic Hepatitis B Dr. Loey Lung-Yi - - PowerPoint PPT Presentation

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Evolution of Liver Fibrosis in Chronic Hepatitis B Dr. Loey Lung-Yi - - PowerPoint PPT Presentation

Apr 13, 2023 17 likes •422 views

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

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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

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Outline

  • Pathogenesis of liver fibrosis in CHB
  • Assessment of liver fibrosis in CHB
  • Concept of fibrosis progression
  • Concept of fibrosis regression
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Outline

  • Pathogenesis of liver fibrosis in CHB
  • Assessment of liver fibrosis in CHB
  • Concept of fibrosis progression
  • Concept of fibrosis regression
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Chronic hepatitis B disease phases

Yuen MF et al. Nat Rev Dis Primers 2018

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Chronic hepatitis B disease progression

Lok ASF. New Eng J Med 2002 McMahon BJ. Hepatology 2009 McMahon BJ. Clin Liver Dis 2010 Acute infection Chronic infection

Liver fibrosis Cirrhosis

Liver failure HCC LT Death

>90% vertical transmission <5% immunocompetent adults ~30% 5-15%

Liver fibrosis

HCC: hepatocellular carcinoma LT: liver transplantation

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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

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Figure adapted from Friedman SL. J Biol Chem 2000

TIMP

Activated HSC

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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

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Outline

  • Pathogenesis of liver fibrosis in CHB
  • Assessment of liver fibrosis in CHB
  • Concept of fibrosis progression
  • Concept of fibrosis regression
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Liver Biopsy: Scoring Systems for Histologic Stage

  • 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.

Appearance Ishak Description Ishak Score1 METAVIR Score2

No fibrosis F0 Fibrous expansion of some portal areas ± short fibrous septa 1 F1 Fibrous expansion of most portal areas ± short fibrous septa 2 F2 Fibrous expansion of most portal areas with occasional portal to portal (P–P) bridging 3 Fibrous expansion of most portal areas with marked bridging (P–P and portal to central [P–C]) 4 F3 Marked bridging (P–P and/or P–C) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis 6 F4

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Liver biopsy: out of favour in clinics

Liver biopsy

Risks and mortality (1:10,000) Sampling error (1 in 50,000) – length & degree of fragmentation Inter- & intra- observer variability (up to 33% discrepancy) Categorical scoring systems

Regev A et al. Am J Gastroenterol 2002

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Methods of assessing liver fibrosis

  • 1. Liver biopsy
  • 2. Serum biomarkers
  • 3. Imaging-based techniques

EASL-ALEH. J Hepatology 2002

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Parikh P et al. Ann Transl Med 2017

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EASL-ALEH. J Hepatology 2015

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.

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Outline

  • Pathogenesis of liver fibrosis in CHB
  • Assessment of liver fibrosis in CHB
  • Concept of fibrosis progression
  • Concept of fibrosis regression
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Fibrosis progression in CHB

Histology Transient elastography

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Factors associated with fibrosis progression in CHB

  • 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

HBV (N=610)

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Liver fibrosis progression in HBeAg + treatment-naïve patients

Wong GL et al. J Gastroenterol Hepatol 2013

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

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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 treatment-naïve patients with metabolic syndrome

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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)

Mak LY et al. Manuscript submitted TN: Metabolic syndrome (OR 4.595, 95% CI: 1.072 – 19.701, p = 0.040) TE: CAP score (OR 1.017, 95% CI: 1.006 – 1.029, p = 0.003)

All patients: Treatment with NA (OR 0.436, 95% CI 0.192 – 0.990, p = 0.047)

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Fibrosis regression in CHB

Histology Transient elastography Serum markers

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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

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Figure adapted from Friedman SL. J Biol Chem 2000

Apoptosis/ return to quiescent stage for activated HSCs Fibrinolysis by MMP, macrophages and Kupffer cells

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Fibrosis regression following antiviral therapy

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Su TH & JH Kao Expert Rev Gastroenterol Hepatol 2015;9(2):141-54

Treatment start

Achievements of the Present Antiviral Treatment

Mortality reduction Transplant need reduction HCC reduction Cirrhosis reduction Fibrosis regression HBsAg seroclearance Histological improvement HBeAg loss-seroconversion HBV DNA negativity ALT normalisation

Short-term goal Medium-term goal Long-term goal

Histological response Serological response Histological response Serological response Virological response Biochemical response Clinical Outcomes

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Long-term ETV lead to reduction of Ishak fibrosis score (N=57)

Long-term = 6 (range, 3-7) years of ETV

Chang TT et al. Hepatology 2010

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)

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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

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Antiviral therapy No antiviral therapy Interval of 512 days 12.9 kPa à 6.6 kPa (P = 0.0001) Interval of 422 days 6.1 kPa à 6.3 kPa (P = 0.0682)

Osakabe K et al. J Gastroenterol 2011.

Use of antiviral therapy led to progressive reduction in LS

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Facciorusso A et al. Dig Liver Dis 2018

Systematic review with meta-analysis

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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

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Histological (Ishak) fibrosis stage improvement and reduction in serum fibrosis marker (M2BPGi) after NA therapy

Mak LY et al. Clin Tranl Gastroenterol 2018

N=54 N=145

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Fibrosis regression following HBsAg seroclearance

Histology Transient elastography

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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

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Reduction in liver fibrosis score after HBsAg seroclearance (N=11)

Fong TL et al. Hepatology 1993

Mean duration of HBsAg seroclearance: 3.9 years

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Lower liver stiffness after HBsAg seroclearance

  • nly if persistent normal ALT

Fung J et al. J Viral Hepat 2011

ALT categories: 1: normal ALT at 1st LSM, high ALT at 2nd LSM 2: high ALT at 1st LSM, normal ALT at 2nd LSM 3: normal ALT at both LSM 4: high ALT at both LSM

N=95 Across 3 years

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Liver stiffness declined progressively with increasing duration of HBsAg seroclearance (N=45)

Mak LY et al. Manuscript submitted

r = - 0.5 (P <0.001)

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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

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Chronic hepatitis B disease progression

Lok ASF. New Eng J Med 2002 McMahon BJ. Hepatology 2009 McMahon BJ. Clin Liver Dis 2010 Acute infection Chronic infection

Liver fibrosis Cirrhosis

Liver failure HCC LT Death

>90% vertical transmission <5% immunocompetent adults ~30% 5-15%

HCC: hepatocellular carcinoma LT: liver transplantation

Antiviral therapy HBsAg seroclearance

Liver fibrosis

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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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Thank you!