6 Riunione Monotematica A.I.S.F NASH malattia epatica, oncologica e cardiovascolare

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1 6 Riunione Monotematica A.I.S.F NASH malattia epatica, oncologica e cardiovascolare Modena, 9 ottobre 2015 Massimo Colombo NAFLD e HCC: caratteristiche distintive Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ Transplant Head Division of Gastroenterology and Hepatology Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy

2 Financial Disclosures Grant and research support: BMS, Gilead Science Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, Alfa Wasserman Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, AbbVie

3 Hepatocellular Carcinoma in NAFLD. Distinctive Features Outline Prevalence and time trends of incidence rates Clinical presentation and pathological features Access to screening & related barriers Outcome of curative therapies Primary prevention: facts or myths?

4 Geographic Distribution of HCC Risk Factors The Bridge Cohort Study Risk factors N. America Europe China Taiwan S. Korea Japan n (%) n = 2,243 n = 3,466 n = 8,538 n = 1,580 n = 1,172 n = 446 HBV 522 (23) 362 (10) 6,575 (77) 987 (63) 884 (75) 64 (14) HCV 876 (39) 1,590 (46) 255 (3) 489 (31) 112 (10) 284 (64) ALD 471 (21) 1,290 (37) 416 (5) 66 (4) 110 (9) 59 (13) NASH 275 (12) 334 (10) 53 (1) 84 (5) 68 (6) 9 (2) Park JH et al, Liver Int. 2015;35:

5 Population-based Study of Incidence Rates and Risk Factors of HCC in the USA, SEER ,748 HCC and non-hcc matched controls (3:1) Cause of chronic liver disease in HCC Independent factors associated with HCC HCV HBV OR (95% CI) 14.1% NAFLD Annual increase of HCC: 9% NAFLD 13% HCV Younossi et al, Hepatology 2015 in press

6 Cohort Studies of Incidence Rates of NAFLD and HCV-related HCC 5-yr incidence 7.1-yr incidence 1-yr incidence Oda et al, J Clin Gastroenterol 2015;8:1-9

7 Prospective Study of HCC in Cirrhotic Patients Evaluated for OLT. The Cleveland Clinic, HCV and 195 NASH patients HCV Alcohol NASH Alcohol No Alcohol No Alcohol Social alcohol intake vs no alcohol Ascha et al, Hepatology 2010;51:1972-8

8 A Retrospective Study of NAFLD Associated HCC Over Time. Newcastle-upon-Tyne From 2.0 to 3.7x10 5 HCC mortality HCC increases : 2-3 fold HCV & alcohol 10 fold NAFLD By 2010 metabolic RFs in 66% HCCs Dyson et al, J Hepatol 2014;60:110-7

9 UNOS Registry: NASH Is Driving Increase in HCC Requiring Liver Transplantation Wong et al, Hepatology 2014;59:

10 Hepatocellular Carcinoma in NAFLD. Distinctive Features Outline Prevalence and time trends of incidence rates Clinical presentation and pathological features Access to screening & related barriers Outcome of curative therapies Primary prevention: facts or myths?

11 Population Study in the US: NAFLD HCC from SEER Registry Modified from Younossi et al, Hepatology 2015 in press

12 Cohort Study: Temporal Trends of NAFLD Related HCC in the Veteran Affairs Population, Same demographic features of NAFLD HCC as those in the SEER population-based study Modified from Mittal et al, Clin Gastroenterol Hepatol 2015;13:

13 Cohort Study: Temporal Trends of NAFLD Related HCC in the Veteran Affairs Population, Modified from Mittal et al, Clin Gastroenterol Hepatol 2015;13:

14 Steatohepatitic Variant of HCC, Well Differentiated Tumor Associated to Metabolic Stigmata Columbia UMC: 22 of 66 (33.5%) HCCs detected in explanted HCV cirrhotic livers Tokyo University: , 293 resected HCCs 120 SH-HCCs (31.4%) in 106 patients Salomao et al, Am J Surg Pathol. 2010;34: Shibahara et al, Histopathology 2014;64:951-62

15 HCC in NASH: Well Differentiated Tumor, often without Cirrhosis Paradis et al, Hepatology 2009;49:851-9

16 Hepatocellular Carcinoma in NAFLD. Distinctive Features Outline Prevalence and time trends of incidence rates Clinical presentation and pathological features Access to screening & related barriers Outcome of curative therapies Primary prevention: facts or myths?

17 Surveillance for HCC as Recommended by AASLD, APASL and EASL STRATEGY AASLD 2011 APASL 2010 EASL 2012* Target population Cirrhosis, CHB 1 NAFLD Viral cirrhosis Cirrhosis, CHB 2 HCV F3 1 Asian males > 40 years and females > 50 years Family history of HCC African/North American blacks > 20 years 2 Active hepatitis Family history of HCC *EASL-EORTC: Evidence 1B/3A recommendation 1A/B Bruix & Sherman, Hepatology. 2011;53: Omata, Hepatol Int. 2010;18;4: EASL-EORTC J Hepatol. 2012;56:908-43

18 Cohort Study: Temporal Trends of NAFLD Related HCC in the Veteran Affairs Population, National cohort from the VA of 1500 patients with HCC Mittal et al, Clin Gastroenterol Hepatol 2015;13:

19 Hepatocellular Carcinoma in NAFLD. Distinctive Features Outline Prevalence and time trends of incidence rates Clinical presentation and pathological features Access to screening & related barriers Outcome of curative therapies Primary prevention: facts or myths?

20 The Magnitude of the Association Between Metabolic Syndrome and Clinical Outcomes Outcome No. of pts Population OR (95% CI) 1 HCC 3,649 USA 2.13 ( ) 1 ICC 743 USA 1.56 ( ) 2 CVD 172,573 Europe & USA 2.18 ( ) 2 Death 1.60 ( ) 1. Welzel et al. Hepatology 2011;54:463-71; 2. Gami et al. J Am College Cardiol 2007;49:

21 Population Study: NAFLD HCC in the US from Factors independently associated with one-year mortality (HCC cohort) Adjusted survival curve by liver disease HR (95% CI) Older age 1.02 ( ) Lower income 1.33 ( ) Unstaged tumor 1.24 ( ) Medicare eligibility disabled/esrd 1.39 ( ) NAFLD 1.21 ( ) Younossi et al, Hepatology 2015 in press

22 Cohort Study: Liver Resection for HCC in Patients with Metabolic Syndrome A multicenter matched analysis with HCV-related HCC Viganò L et al, J Hepatol 2015;63:93-101

23 Cohort Study: Curative Treatment for HCC in NASH vs HCV and ETOH Liver Disease, Pittsburg Overall Survival Recurrence Free Survival Reddy et al, Hepatology 2012;55:

24 Cohort Study: Curative Treatment for HCC in NASH vs HCV and ETOH Liver Disease, Pittsburgh Reddy et al, Hepatology 2012;55:

25 Clinical Implications of NAFLD in HCC Patients with NAFLD and HCC - More frequently subjected to resection since more frequently non cirrhotic Comorbidities and negative effect of steatosis on - Liver regeneration - Susceptibility to ischemia Selzner & Clavien, Semin Liver Dis. 2001;21:105-13

26 Cohort Study: Steatosis and Surgical Site Infections (SSI) University Hospital of Bern 116 liver resections 126 hepatic & 115 colorectal resections SSI (%) Liver attenuation (HU) Kurmann et al, Surgery 2014;156:109-16

27 Probability of Waitlist Mortality and Receipt of Liver Transplant at 90 Days and at 1 Year Wong et al, Gastroenterology 2015;148:547-55

28 Hepatocellular Carcinoma in NAFLD. Distinctive Features Outline Prevalence and time trends of incidence rates Clinical presentation and pathological features Access to screening & related barriers Outcome of curative therapies Primary prevention: facts or myths?

29 A Prospective Study of Physical Activity and Prevention of HCC, Taiwan 428,584 (HCV+/-) followed-up prospectively: 1668 HCC in 8.5 years Physiscal activity (MET-hr) <3.75 3,75-7,49 >7.5 Wen et al, J Natl Cancer Inst. 2012;104:

30 Metformin and Prevention of HCC. A Meta-analysis in Type 2 DM Metformin reduces the risk to develop HCC by 70% in DM Retrospective analysis of 172 diabetic patients with cirrhosis with a median survival of 12 years No episodes of lactic acidosis Zhang e tal, J Clin Endocrinol Metab. 2012;97: Zhang et al Hepatology 2014

31 Distinctive Epidemiological and Clinical Features of NAFLD-HCC Incidence rates of NAFLD-HCC are on the rise in different geographical areas. Paucity of population-based studies. NAFLD-HCC is associated with older age, cryptogenic cirrhosis, obesity, diabetes and heart disease. No peculiar molecular stigmata. Unique pathological feature of SH-HCC. NAFLD-HCC has shorter survival times than virus-related liver tumors, often due to late diagnosis (lack of screening). Same therapeutic algorithm and response to therapy as for other etiologies, however, limited access to OLT. Primary prevention possible through life style interventions, yet needs validation. Secondary prevention (screening) to be implemented.