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
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
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) 0,0 0 1 2 3 4 Fibrosis stages No/mild fibrosis Charlotte, Human Pathol 2010
Bed-Side Risk Factors for Severe Fibrosis in NASH Age > 45-50 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
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
NAFLD STEATOHEPATITIS STEATOSIS F0 F2 F1 F3 F4 Cirrhosis No or minimal fibrosis
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
Progression from NAFL to NASH Initial biopsy (N=25) 25 NAFL Follow-up biopsy 9 8 8* 8 1 5 3 2 5 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
Impact of inflammation on disease progression Argo, J Hepatol 2009 Pais, J Hepatol 2013
NAFL NAFLD NASH Steatosis alone Steatosis & inflammation NASH Potential for progression
% 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 < 25 25-30 30-35 35-40 >40kg/m²
% 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 < 25 25-30 30-35 35-40 >40kg/m²
35,781 primary LT in the US from 2001-2009 1959 for NASH NASH increased from 1.2% in 2001 to 9.7% in 2009 3 rd most common indication for LT in the US Charlton, Gastroenterology 2011
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
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
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
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
BMI and Cause-specific mortality 57 prospective studies including 900,000 adults (Europe, NorthAm) PSC, Lancet 2009 Death by liver cancer HR 1.47 (1.26-1.71)
Emerging Risk Factor Collaboration Study Individual participant data from 97 prospective studies with >1 yr of f/u. 715061 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
Hazard Ratios for Death from Non-cancer Non-vascular causes HR of death from non-cancer, non-cv in diabetics : 2.28 (1.9-2.74) ERFC, NEJM 2011
Obesity and mortality by cirrhosis Prospective cohort of 1.23 M middle aged UK women +28% in 1996-2001 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
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
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
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