Prognosis of NASH VII Workshop Intenracional de Actualizaçao em Hepatologia, Aug 29th 2014

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1 Prognosis of NASH VII Workshop Intenracional de Actualizaçao em Hepatologia, Aug 29th 2014 Vlad Ratziu, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

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4 NASH : a severe hepatic disease? Proof of concept presentation Hepatocellular carcinoma Significant fibrosis and fibrosis progression Survival Potential for Severe clinical outcomes Cirrhosis and cryptogenic cirrhosis Liver failure

5 Area of fibrosis (%) Fibrotic potential : NAFLD vs. HCV AF by micromorphometry for equivalent architectural changes 20,0 16,0 12,0 8,0 4,0 P< 0.03 * NAFLD (Brunt stage) HCV (METAVIR stage) 0, Fibrosis stages No/mild fibrosis Charlotte, Human Pathol 2010

6 Bed-Side Risk Factors for Severe Fibrosis in NASH Age > yrs Diabetes BMI > 27 kg/m² Arterial HTN Hypertriglyceridemia (TG > 1.7 mmol/l) ALT>2N AST/ALT > 1 Angulo, Hepatology 1999 Ratziu, Gastroenterology 2000 Dixon, Gastroenterology 2001

7 Bridging fibrosis is an independent predictor of liver deaths 257 Pts; median f/u 12 yrs; end-point : liver-related mortality (LRM) FIBROSIS STAGE Younossi, Hepatology 2011

8 NAFLD STEATOHEPATITIS STEATOSIS F0 F2 F1 F3 F4 Cirrhosis No or minimal fibrosis

9 Progression from NAFL to NASH 70 NAFLD patients with repeat liver biopsy Mean follow-up : 3.7 years (s.d. 2.1) Pais, J Hepatol 2013

10 Progression from NAFL to NASH Initial biopsy (N=25) 25 NAFL Follow-up biopsy 9 8 8* NAFL Ballooning progression (* Bal score 1; Bal score 2) Progression to bridging fibrosis Patients with disease progression were older (58 vs 46 yrs, p=0.04) and had a higher BMI (30.1 vs 26.2 kg/m²) and more often diabetes (43vs 19%) than those without progression. Pais, J Hepatol 2013

11 Impact of inflammation on disease progression Argo, J Hepatol 2009 Pais, J Hepatol 2013

12 NAFL NAFLD NASH Steatosis alone Steatosis & inflammation NASH Potential for progression

13 % with cirrhosis NASH is a major cause of cryptogenic cirrhosis (CC) High prevalence of metabolic risk factors in CC UNOS database (N=19,271): increasing BMI translates into a higher prevalence of CC HCV Alcoho < >40kg/m²

14 % with cirrhosis NASH is a major cause of cryptogenic cirrhosis (CC) High prevalence of metabolic risk factors in CC UNOS database (N=19,271): increasing BMI translates into a higher prevalence of CC HCV Alcoho CC < >40kg/m²

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16 35,781 primary LT in the US from for NASH NASH increased from 1.2% in 2001 to 9.7% in rd most common indication for LT in the US Charlton, Gastroenterology 2011

17 Progression to liver-related death N=152 NASH-cirrhosis & 150 HCV-cirrhosis Sanyal, Hepatology 2006 Child A NASH HCV Child B Child C N=27 CC/NASH-cirrhosis & 85 matched HCV-cirrhosis Ratziu, Hepatology 2002 HCV Child A Child B,C NASH

18 Progression to liver-related death N=152 NASH-cirrhosis & 150 HCV-cirrhosis Sanyal, Hepatology 2006 Child A NASH HCV Child B Child C N=27 CC/NASH-cirrhosis & 85 matched HCV-cirrhosis Ratziu, Hepatology 2002 HCV Child A Child B,C NASH

19 Causes of death in NASH cirrhosis Same as in any other cause of cirrhosis Same prognostic value of MELD, Child-Pugh, N=152 NASH-cirrhosis 8 yrs f/u 29 Deaths COMPETITIVE RISK Cardiovascular N=8 Other N=2 Liver failure N=19 Sepsis +++ Variceal ++ hemorrhage HCC + Sanyal, Hepatology 2006

20 NASH : effect on survival Survival vs. the general population STEATOSIS NASH Liver-related mortality Same survival as the general population Cardiovascular mortality Cirrhosis : an independent risk factor of death Matteoni, Gastro 1999, Adams, Gastro 2005, Ekstedt, Hepatol 2006, Ong, J Hepatol 2008, Dunn AJG 2008, Sorderberg, Hepatology 2010

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22 BMI and Cause-specific mortality 57 prospective studies including 900,000 adults (Europe, NorthAm) PSC, Lancet 2009 Death by liver cancer HR 1.47 ( )

23 Emerging Risk Factor Collaboration Study Individual participant data from 97 prospective studies with >1 yr of f/u participants with no preexisting vascular disease Diabetes : 40,116, Non-diabetics : 67,4945 Subsequent cause specific death recorded during follow-up 41,320 deaths from cancer, 44,407 from vascular disease, 27,661 from other causes, 9817 of unknown or ill-defined cause ERFC, NEJM 2011

24 Hazard Ratios for Death from Non-cancer Non-vascular causes HR of death from non-cancer, non-cv in diabetics : 2.28 ( ) ERFC, NEJM 2011

25 Obesity and mortality by cirrhosis Prospective cohort of 1.23 M middle aged UK women +28% in risk per 5 u BMI 56 yr-old; 36% overweight; 18% obese 6.2 person/year f/u Alcohol and smoking increase the absolute risk 1811 first hospital admissions for cirrhosis or death by cirrhosis Cirrhosis morbi/mortality : 42% alcohol 17% overweight (BMI>25) Liu, BMJ 2010

26 NAFLD Center stage of the metabolic syndrome? Hypertension Cardiovascular Prevalence essential HTN Incident diabetes Insulin requirements NAFLD Diabetes Endothelial & coronary dysfunction Carotid plaques Impaired ventricular fct and metabolism CV events

27 Impact of NAFLD on mortality in diabetic patients Community based study in Olmsted County, Mn, USA DT2 + NAFLD (N=116) DT2 no NAFLD (N=231) F/u (yrs) 9.2 (5.2) 11.7 (5) Liver related death 5 (19%) 0 Malignancy 9 (33%) 13 (18%) NAFLD independent risk factor for overall mortality Increased risk for liver-related mortality and neoplasiarelated mortality Adams, AM J Gastro 2010

28 Closing arguments : will NASH be the next severe hepatic disease? Fibrosis potential similar to HCV NASH vs steatosis vs steatosis + inflammation Reduced survival, increased liver-related deaths Disease progression : is steatohepatitis important or is it only about fibrosis? End-stage liver disease due to NASH is increasingly recognized rising cause of LT Under-recognized data of hepatic mortality in the obesity and diabetes litterature Extrahepatic complications of fat and impact of NASH on mortality in diabetics