Healthy Liver Cirrhosis

Transcription

1 Gioacchino Angarano Clinica delle Malattie Infettive Università degli Studi di Foggia Healthy Liver Cirrhosis Storia naturale dell epatite HCVcorrelata in assenza di terapia Paestum Maggio 24

2 The Natural History of Hepatitis C Infection Difficulties usually asymptomatic onset usually asymptomatic course long disease duration 3-4 yrs often presence of co-factors

3 Clinical Outcomes Acute HCV infection subclinic acute hepatitis

4 Outcome of Acute Hepatitis C Healthy carrier? 1-2%? 5-85% Chronic Hepatitis 15-5% Spontaneous viral clearance

5 Primary HCV Infection c1 NS3 c22 HCV-RNA ALT Anti-HCV (EIA) HCV RNA in serum within 1-2 weeks after exposure Anti-HCV antibodies in serum within 3-2 weeks (average 7) ALT increase after 4-12 weeks Clinical symptoms in 1-3% Fulminant hepatitis is rare weeks years exposure

6 Course of Acute hepatitis C Outcome Spontaneous resolution in about one third of the patients No patients = 4 Median Follow-up = 35 months (range 6-68) 3% Self-limited hepatitis 7% Chronic evolution Santantonio et al Digest Liver Dis 23

7 Studies Demonstrating High Rates of Spontaneous Recovery in HCV Infection Author Country % Recovery Setting Kenny Walsh Wiese Vogt Rodgers Gerlach Ireland Germany Germany Australia Germany Contaminated Rh Ig Contaminated Rh Ig TAH* - children Community acquired Symptomatic disease

8 Acute Hepatitis C Factors that may influence the evolution Virus Quasispecies evolution Gender Host Age at onset Source of infection Immunocompetence Genetic profile Symptomatic disease

9 Natural Course of Acute hepatitis C Prognostic factors icteric AHC Jaundice significantly associated with selflimited hepatitis 55% Chronicity 45% Resolution No correlation with: Genotype, Viral load at presentation, Sex, Mode of trasmission anicteric AHC 15% Resolution 85% Chronicity Santantonio et al Digest Liver Dis 23

10 Clinical Outcomes Acute HCV infection subclinic acute hepatitis ~3% ~7% Complete Recovery Chronic HCV hepatitis

11 Strategies for determining Natural History of Chronic hepatitis Initial infection Early phase Chronic hepatitis Late phase chronic Hepatitis (cirrhosis) 2 to 4 years Retrospective Studies Prospective Studies Retrospective prospective (non concurrent) cohort studies

12 Long- Term outcome of HCV infection Retrospective Studies Author Country Pts Interval from Cirrhosis HCC Liver exposure (yrs) (%) (%) Death (%) Kiyosawa Japan NR Tong USA Yano Niederau Japan Germany NR^ mean 42% NR 2. NR 3.7 Gordon* Usa NR Gordon** Usa NR * Transfusion ; ** Community Acquired; ^ Not reported

13 Long- Term outcome of HCV infection Prospective Studies Author Country Pts Interval from Cirrhosis HCC Liver exposure (yrs) (%) (%) Death (%) Di Bisceglie USA Koretz Mattson USA Sweden mean 11% 1.3 NR Tremolada Italy

14 Long- Term outcome of HCV infection Retrospective Prospective Studies Author Group Pts Interval from Cirrhosis HCC Liver exposure (yrs) (%) (%) Death (%) Vogt Children Kenny-Walsh Young women Wiese Seeff* Young women Young men <6% Thomas IDU Rodgers Comm acq Seeff** PTH *Community-acquired **Transfusion

15 Progression to cirrhosis after 2-year HCV infection by study recruitment % (11-37%) 22% (18-26%) 57 studies % (4-1%) 4% (1-7%) Post-transfusion hepatitis (5) Liver Clinics (33) Community-based cohorts (9) Blood Donors (1) Mean age Freeman et al Hepatology 21

16 PROGRESSION OF HEPATIC FIBROSIS IN CHRONIC HEPATITIS C 4 Men > 4 yr Alcohol > 5 gr/die Fibrosis Rapid Medium Slow Women < 4 yr Alcohol < 5 gr/die Years Poynard et al Lancet 1997;349:

17 Potential Cofactors As Determinants of Disease Progression Viral factors Host Factors External Factors Viral Load Viral Genotype Multiplicity of quasispecies Age at infection Gender Duration of infection Disease expression Immune deficiency Genetic susceptibility Coinfections (HIV, HBV) Co-morbid conditions e.g., hemochromatosis, non alcoholic steatohepatitis, Alcohol abuse Diet Smoking Drugs Hepatotoxins Environmental contaminants

18 HCV: natural history Alcohol Increased risk of cirrhosis in HCV-infected patients who drink 3-6g alcohol per day Sustained virological response to IFN is lower in patients with a recent history of alcohol abuse Increased quasispecies and viremia levels in alcoholics Alcohol and HCV are sinergistic in accelerating hepatic fibrosis in patients through immune related reactions and increased oxidative stress Morgan et al Alcohol Clin Exp Res 23

19 HCV: natural history HBV coinfection: More severe liver damage More rapid clinical course High risk for HCC Lower IFN therapy response

20 Liver histopathology in patients with hepatitis B/C and hepatitis B/C/D compared with matched control subjects with HCV alone Total Scheuer score Hepatitis C (n=24) Hepatitis C (n=24) p = <.1 Hepatitis B+C (n=12) Hepatitis B+C+D (n=12) Weltman et al J Viral Hepat 1995

21 Risk for HCC according to Alcohol Intake and the Presence of HCV and HBV Infection Alcohol intake (g/day) -6 > 6 Cases/Controls (no.) O.R. Cases/Controls (no.) O.R. Neither 3/ / HCV infection 95/ / HBV infection 41/ / Donato et al., Am J Epidemiol 22

22 Rates of HCC in Relation to Etiology of Cirrhosis Cumulative probability of HCC (%) HBsAg+/anti-HCV+ p =.2 Alcohol abuse Anti-HCV pos HBsAg pos All negative Months Benvegnù et al,. Cancer 1994

23 Occult HBV infection in patients with chronic hepatitis C Pts = 2 HCV positive Anti-HBc positive Anti-HBc negative Histologic findings Minimal changes Chronic hepatitis Cirrhosis Liver HBV DNA Positive N=66 (33%) 46 2 Negative N=134 5 (4%) 44 (67%) 13 (77%) 22 (33%) 26 (19%) p ns ns.4 Occult HBV infection may interfere with the clinical outcome of chronic hepatitis C and favor or accelerate the evolution to cirrhosis Cacciola et al N Engl J Med 1999

24 Fibrosis Grade (METAVIR) Liver Fibrosis Progression: Influence of HIV Coinfection HIV positive (n = 122) HIV negative (n = 122) Duration of HCV Infection (yr) Patients matched for sex, risk factors, age,age at HCV contamination, age at liver biopsy and daily alcohol consumption. Benhamou Y, et al. Hepatology. 1999;3:154.

25 Increased Risk of Cirrhosis and ESLD in HIV/HCV-Coinfected Patients. META-ANALYSIS Graham CS Clin Infect Dis. 21

26 F F1 F2 F3 F4 4-6 anni 1-15 anni 1-15 anni 4-6 anni Coinfezione HIV-HCV CD4 < 5 5 anni

27 Liver histology among 159 HCV carriers with persistently normal ALT* (Italian prospective study of the asymptomatic C carriers) Minimal CH 34% Mild CH 44% Normal 17% Cirrhosis Mod/severe 4% 1% * (ALT every 3 months over a 12-month period) Puoti et al J Hepatol 22

28 Predictive Value of ALT Levels for Histologic Findings in Chronic Hepatitis C: a European Collaborative Study METAVIR Fibrosis Score Normal ALT Elevated ALT 35% 2% 52% 12% 1% 24% 51% 17% 8% = no fibrosis, 1= portal fibrosis without septa, 2= portal fibrosis with few septa, 3= septal fibrosis without cirrhosis, 4= cirrhosis Pradat et al Hepatology 22

29 Natural history of HCV carriers with persistently normal ALT Prospective studies with histological follow-up Persico et al Gastroenterology 2 Martinot-Peignoux et al Hepatology 21 Very slow or no fibrosis progression

30 Chronic Hepatitis C: Progression to Cirrhosis Baseline Fibrosis 1% 8% Cirrhosis 6% 4% Severe Moderate Mild 2% Years Adapted from Yano M et al. Hepatology. 1996;23:1336.

31 Survival in compensated cirrhosis C Reference Area Pts (n) Median age (yrs) Median follow-up (yrs) 5-year survival Niederau 1998 Germany Hu 1999 U.S.A Degos 2 France Eurohep 22 Europe % 8 survival decompensation HCC years Eurohep, Am J Gastroenterol 22; 97:

32 Compensated cirrhosis type C independent factors affecting survival multivariate analysis (Cox s model) Factors prognosis worse if p value age gender albumin bilirubin platelets oesophageal varices older male < 35 g/l > µmol/l < 13 x 1 9 /l present Fattovich et al Gastroenterology 1997; 112: Degos et al Gut 2; 47:

33 Development of decompensation in HCV-related cirrhosis (ascites, jaundice, encephalopathy, variceal bleeding) Reference Area patients Child's Mean Incidence 4 to 5 yrs (no.) grade follow-up 1 risk (%) (yrs) person/yrs 1. Eurohep Europe 136 A Serfaty France 13 A/B Hu U.S.A. 112 A/B Am J Gastroenterol 22; 97: Hepatology 1998; 27: Hepatology 1999; 29:

34 Incidence of HCC in HCV-related Cirrhosis Authors Country 3 yrs 5 yrs 1 yrs Fattovich 1997 Europe 3% 7% 14% Chiaramonte 1999 Italy 7% 2% 28% Benvegnù 1994 Italy 2.8% 11.5% 3% Ikeda 1993 Japan 1% 21% 53% Yoshida 1999 Japan 12.5% 2% 6%

35 Clinical Outcomes Year Acute HCV infection subclinic acute hepatitis Increasing Fibrosis ~ 3% Complete Recovery ~2% Cirrhosis ~ 7% Chronic HCV hepatitis ~8% Asymptomatic Year 3 4-5% / yr Decompensated cirrhosis Hepatocellular Carcinoma 1-5% / yr