Cirrhosis is different from Fibrosis

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1 Riunione Monotematica AISF 2016 «The Future of Liver Disease: Beyond HCV is there a Role for Hepatologist» Milan 13 th -14 th 2016 Cirrhosis is different from Fibrosis I have not disclosures to declare for this presentation This presentation does not deal with drugs under study or for off-label use Gennaro D Amico UOC Gastroenterologia Ospedale V Cervello Palermo gedamico@libero.it

2 Fibrosis and cirrhosis Liver fibrosis results from the perpetuation of the normal wound-healing response, resulting in an abnormal continuation of fi brogenesis (connective tissue production and deposition) Cirrhosis is an advanced stage of liver fibrosis with nodular regeneration surrounded by dense fibrotic septa, parenchymal extinction and collapse of liver structure, together causing distortion of hepatic vascular architecture with shunting of blood supply directly into the hepatic outflow Shuppan D. Lancet 2008; 371:

3 Fibrosis may progress to Cirrhosis 3

4 Progression of fibrosis in HCV chronic infection Median estimated time to cirrhosis 30 yrs (28-23) Poynard T. Lancet 1997;349:

5 Fibrosis progression to cirrhosis (Fib-4) Butt AA. JAMA Intern Med 2015;175:

6 LS and survival 1457 chronic hepatitis C consecutive patients D'Amico SR 2016 Verginol J. Gastroenterology 2011;

7 Survival according to the presence of cirrhosis Modified from Niderau C HEPATOLOGY 1998;28:

8 Severity of fibrosis and HVPG Nagula S. J Hepatol 2006;44:

9 Histological stages of cirrhosis 9 Subdividing METAVIR stage 4 a subclassification of cirrhosis has been proposed as stage 4A, 4B and 4C based on thikness of septa and size of nodules Kutami R. Hepatology 2000; 32:407 Picture from RastogiA. Histopathology 2013;62:

10 Natural history of cirrhosis Histological stages correlate with CSPH and clinical stages 10 Clinically significant portal hypertension (CSPH) Clinical stages Kim MY J Hhepatol 2011;55:

11 Increasing fibrosis Clinical stages of cirrhosis: a comprehensive view Compensated cirrhosis 1 No CSPH 2 CSPH No varices 3 Varices Decompensated cirrhosis 4 Bleeding 5 First non bleeding decompensation 6 Any second decompensation Death 7 End Stage Infections Renal failure AoCLF 11

12 Fibrosis may regress after etiological cure Regression of fibrosis in HCV cirrhosis after SVR Other causes of CLD for which regression of fibrosis has been documented D Ambrosio R HEPATOLOGY 2012;56: HBV Alcohol NAFLD /NASH Autoimmune Hemocromatosis Secondary biliary cirrhosis Wilson 12

13 Fibrosis outcome after PegIFN based treatment for chronic hepatitis c (3010 pts from 4 RCTs) Regression Of cirrhosis 75/153 Poynard T. Gastroenterology 2002;122:

14 HVPG reduction in HCV cirrhosis 6 months after SVR 6-9 mmhg Subclinical PH mmhg CSPH 16 mmhg CSPH Mandorfer M. J Hepatol 2016;65:

15 NSBB in patients with CSPH or subclinical PH Subclinical PH CSPH Villanueva C. HEPATOLOGY 2016;63:

16 Proposed role of macrophages in hepatic fibrogenesis and fibrosis regression Ramachandran P. Semin Liver Dis 2015;35:

17 Regression of cirrhosis 1.Regeneration of existing nodules Wanless IR APLM 2000;124:

18 Micro to macronodular regression Wanless IR APLM 2000;124:

19 Regression of cirrhosis 2. Formation of new nodules: BUDS Wanless IR APLM 2000;124:

20 Stem-like cholangiocytes in repopulation of parenchimal extinction regions Stueck AE. Hepatology 2015;61:

21 Histologic features of regressed cirrhosis Thin or incomplete fibrous septa No shunting vessels expanding from portal tract Partial or full restoration of lobular architecture Some portal tract or central vein visible Lack of ductular proliferation Cirrhosis does not regress to normal: venous obstruction, arterialization and incomplete settal cirrhosis often remain Regression of cirrhosis Cirrhosis always reversible? Is there a no return point? Extensive cross-linking fibrosis Elastin rich fibrosis Long lasting fibrosis Thick fibrosis Dense acellular/paucicellular ECM resistance to apoptosis of HSCs/myofibroblasts 21 Bedossa P. Surg Pathol 2013;6: Wanless IR APLM 2000;124: Friedman S Hepatology 2006;43:S82-S88 Issa R. Gastroenterology 2004;126:

22 Outcome of advanced HCV fibrosiscirrhosis after SVR in Scotland N=1824 (cirrhosis 5.9%) Standardized Mortality Ratio 1.86( ) Innes H J Hepatol 2016; in press 22

23 Outcome of compensated HCV cirrhosis following SVR 181 patients observed at 3 different centres in Italy survival decompensation HCC Bruno S. J Hepatol 2016, 23

24 Risk of recurrence of hepatocellular carcinoma after DAA therapy Reig 27% in 6 months Cammà, same data 7% and 13% at 6 and 12 months Zero-time=HCC cure Reig M. JH 2016;65: Cammà C. JH 2016;65:

25 Risk of recurrence of hepatocellular carcinoma after DAA therapy Terrault NA J Hepatol 2016;65:S120 S129 25

26 Incidence and progression of varices in HCV cirrhosis according to SVR 26 Incidence Progression No SVR SVR Di Marco V. Gastroenterology 2016;151:

27 SVR in decompensated HCV cirrhosis 27 SVR MELD >2 % Decomp Adverse outcome NO N=86 YES N= Foster GR J Hepatol 2016;64:

28 Delisting of LT candiates for HCV cirrhosis following SVR Belli LS. J Hepatol 2016;65:

29 Regressing Increasing fibrosis fibrosis Clinical stages of cirrhosis: a two way course? Compensated cirrhosis 1 No CSPH 2 CSPH No varices 3 Varices Decompensated cirrhosis 4 Bleeding 5 First non bleeding decompensation 6 Any second decompensation Death 7 End Stage Infections Renal failure AoCLF 29

30 Conclusions 1. fibrosis regression Fibrosis without cirrhosis is not associated with significant liver related manifestations and SVR may halt fibrogenesis and prompt fibrolysis SVR in compensated cirrhosis may result in regression of fibrosis and even in reversal of cirrhosis with marked reduction of clinically significant events However, in a proportion of patients, disease may still progress to decompensation and HCC In decompensated cirrhosis functional improvement may follow SVR, although long-term benefit still needs to be defined 30

31 Conclusions 2. Suggested management SVR F0, F1: no specialized follow-up needed F2: clinic visits every 1 to 2 years, depending on risk factors for progression F3 and compensated F4: clinic visits every 6 months; endoscopy every 3 years; US every 6 months for HCC F4 decompensated: clinic visit every 3 months (or more often complications require) Check fibrosis stage (LSM, serological markers) every 1-2 yrs HCV-RNA testing every 1-2 year in subjects at risk of re-infection Terrault NA J Hepatol 2016;65:S120 S129

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