Ruolo delle indagini strumentali nella stadiazione dell epatite cronica

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1 HCV E IL RUOLO DEL SISTEMA IMMUNITARIO: L IMPATTO DEI NUOVI FARMACI Ruolo delle indagini strumentali nella stadiazione dell epatite cronica Maria Vinci SC di Epatologia e Gastroenterologia Ospedale Niguarda Milano

2 Storia naturale dell infezione da HCV 30anni Sesso femminile Infezione in giovane età Fegato normale Infezione acuta Infezione cronica Epatite cronica cirrosi Rischio di HCC 20anni Alcol,steatosi e/or IR,,coinfezioni,sesso maschile, emosiderosi, infezione in età più avanzata, bassi livelli di vit.d (?) Modified from Lauer et al., N Engl J Med 2001;345:41-52

3 Transition from compensated to decompensated cirrhosis Chronic liver disease Compensated cirrhosis Development of clinical complications Variceal hemorrhage Ascites Encephalopathy Jaundice Decompensated cirrhosis Death Annual rate of decompensation: 4.6% Child Pugh score and MELD usually used to determined the severity of liver disease in patients with cirrhosis Annual progression rate from decompensated HCV cirrhosis to HCC: - 1.7% (women) - 3.6% (men)

4 Survival is significantly greater in compensated vs. decompensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Months D Amico et. al., J Hepatol 2006;44:217.

5 Survival outcomes for All-Cause Mortality, Liver- Related Mortality, LT,HCC and Liver Failure in pts with CHC and advanced fibrosis with or without SVR

6 Why do we need to evaluate fibrosis? Significant fibrosis? Indication of treatment Severe fibrosis or cirrhosis? Treatment Hepatocellular carcinoma screening Oesophageal varices screening

7 AGENDA Ruolo delle indagini strumentali - Nella stadiazione della malattia epatica - Come indicatori di prognosi nella cirrosi

8 Staging liver fibrosis Fibroscan Serum markers of liver fibrosis Staging of fibrosis Liver biopsy Hepatic venous pressure gradient (HVPG)

9 EASL Recommendations on Treatment of Hepatits C 2014 Fibrosis stage can be assessed by non- invasive methods initially, with liver biopsy reserved for cases where there is uncertainty or potential a additional etiologies

10 Biopsia epatica : indicazioni Presence and localization of specific lesions (inflammation, steatosis, siderosis)

11 Biopsia epatica Accettabilità del paziente Costi e disponibilità Morbidità Mortalità Complicanze clinicamente significative 1: di tessuto epatico 0.3 % Accuratezza: Campionamento Esperienza del patologo

12 Biopsia epatica: campionamento e variabilità della fibrosi

13 Biopsia epatica: errore di campionamento Variabilità del grading e staging tra lobo epatico destro e sinistro in HCV % % % % 2% Variazione grading Variazione staging cirrosi in un lobo e F nell'altro Regev et al, Am J Gastroenterol; 2002

14 Biopsia epatica Impatto della lunghezza del frustolo bioptico sul n. degli spazi portali e sulla valutazione del «grading» e dello «staging» (G.Colloredo et al J Hepatol 2003) Lunghezza del frustolo 1 cm 1.5 cm 3cm P N. Spazi Portali Completi Incompleti 6.4 ± ± ± ± ± ± 1.1 <0.001 <0.001 Grading Lieve Moderata Severa 133 (86.6%) 28 (17.4%) 0 97 (60.2%) 63 (39.1%) 1 (0.6%) 80 (49.7%) 62 (38.5%) 19 (11.8%) <0.001 Staging Lieve Moderata Severa 129 (80.1%) 24 (14.9%) 8 (4.9%) 110 (68.3%) 39 (24.2%) 12 (7.4%) 95 (59%) 48 (29.8%) 18 ( 11.2%) <0.002

15 Biopsia epatica Impatto del diametro dell ago da biopsia sul n. degli spazi portali Lunghezza del frustolo 3cm 1.5 cm Φ 1.4 mm Φ 1 mm Φ 1.4 mm Φ 1mm N. Spazi Portali Completi Incompleti 22.4 ± ± ± ± ± ± ± ±0.9 (G.Colloredo et al J Hepatol 2003)

16 Biopsia epatica 365 pazienti sottoposti a biopsia epatica 6% [VALORE] 9% 11% 74% Confirmed diagnosis Added diagnosis Changed diagnosis Changed management Spycher et al BMC Gastroenterology 2001

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18 Liver stiffness Transient elastography (FibroScan ) US Transducer : 3.5 MHz Vibrator: mild amplitude and low frequency (50 Hz) elastic waves Propagation speed of elastic waves: directly related to tissue stiffness

19 Confounding factors for liver stiffness Others? Acute Inflammation Coco et al. J Viral Hepat 2007 Arena et al. Hepatology 2008 Sagir et al. Hepatology 2008 Liver congestion Millonig et al. J Hepatol 2010 Extra-hepatic cholestasis Millonig et al. Hepatology 2008

20 FibroScan: Quality criteria for reliable results Median liver stiffness Interquartile range <30% of median value SR 100% Success Rate At least 60% Number of valid measurement At least 10

21 Applicability of transient elastography Failure 3.1% Obesity Unreliable 15.8% SR < 60% 8.1% FibroScan Valid shot = 0 not applicable VS < % in 20% of cases Operator experience IQR/LSM > 30% 9.2% N=13669 examinations Castéra et al. Hepatology 2010; 51:

22 TE- Correlation with liver fibrosis

23 Liver stiffness and cirrhosis (assessed by Metavir scoring system) F0F1 F1F2 F2 F3 F3F4 F kpa In HCV patients the most validated TE cutoff points are : 7.1 kpa to identify significant fibrosis 12.5 kpa to recognize cirrhosis

24 Transient elastography: diagnostic accuracy N. of studies N. of patient F2 Auroc F3 F4 Cut - F2 off F3 (kpa) F4 Talwalkar et al* Stebbing et al** Friedrich- Rust et al Tsochatzis et al# Chon et al N/A 0.96 N/A N/A N/A N/A N/A N/A N/A N/A *Clin Gastroenterol Hepatol 2007 ** J Clin Gatroenterol 2010 J Viral.Hepatol 2012 #J Hepatol Plos One 2012

25 GGT Bilirubin ALT Haptoglobin Apolipoprotein A1 α2 macroglobulin Platelet count Prothrombin time Hyaluronate Biomarkers False positive values with hemolysis, inflammation, Gilbert s syndrome

26 Score Variables Performance in HCV patients (original Significant fibrosis( F2) Cirrhosis reference) AUROC Sens Spec AUROC Sens Spec FIBROTEST GGT, Haptoglobin bilirubin, ApoA1, alfa- 2 macroglob. FORNS Age, GGT,Cholest Platelets % 96% % 81% % 94% % 91% APRI AST,Platelets % 95% % 94% FIB4 Age, AST, ALT Platelets FIBROMETER Platelets, PT, AST Age,urea,macroglob, hyaluronate HEPASCORE age,sex,alfa2 macrog, GGT Hyal.,bil % 79% % 92% % 81% % 79% % 86% Chou et al Ann Intern Med 2013

27 Combination of markers: The Sequential Algorithm for Fibrosis Evaluation (SAFE) Sebastiani et al Hepatol 2009 Biopsia epatica evitata nel 36% dei casi: paz con fibrosi F2 senza cirrosi pazienti con cirrosi Dati discordanti nel 9.9% (fibrosi severa) e nel 7.5% (cirrosi)

28 The Bordeaux Algorithm Castera et al J of Hepatol 2010

29 The Bordeaux vs SAFE algorithm N=302 chronic hepatitis C 71.9% of liver biopsies avoided (vs 48% with SAFE) 78.8% of liver biopsies avoided (vs 74.8% with SAFE) Castera et al J of Hepatol 2010

30 Combination of FibroScan and blood test: well-classified patients and theoretically avoided liver biopsies Zarski JP, et al. J Hepatol 2012

31 Liver fibrosis The results of non-invasive tests for the diagnosis of significant fibrosis and cirrhosis are approximately equal However, combination of Fibroscan with a blood test markedly improves the percentage of wellclassified patients for the diagnosis of significant fibrosis

32 AGENDA Ruolo delle indagini strumentali - Nella stadiazione della malattia epatica - Come indicatori di prognosi nella cirrosi

33 Natural History of chronic liver disesase Increasing liver Fibrosis Increased portal Pressure HVPG 6-10 mmhg Increasing liver Fibrosis HVPG>10mmHg Hyperdinamic circulation Increasing portal pressure HVPG > Increasing hyperdinamic circulation Chronic liver disease Compensated cirrhosis Decompensated Cirrhosis Further Decompensate cirrhosis No varices Varices Variceal hemorrage Ascites Encephalopaty Jaundice Recurrent variceal hemorrage Refractory ascites Hepatorenal sindrome Bacterial infection Garcia-Tsao G Dis Mark 2011 ; 31:

34 HVPG is the goal standard technique to diagnosis of portal hypertension and its severity SAFE ACCURATE REPRODUCIBLE WELL ACCEPTED SPECIFIC TRAINING INVASIVE

35 Hepatic vein catheterization

36 HVPG 10 mmhg is an independent predictor of decompensation in patients with compensated cirrhosis 1.0 Probability of decompensation (ascites, VH, HE)) 0.8 Log rank test: P<0.01 HR 3.95 ( ) Baseline HVPG 10mmHg % NPP, i.e. patients with an HVPG <10 mmhg have a 90% chance of not developing clinical decompensation in a 4-year period 0.2 Baseline HVPG <10mmHg months Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:

37 In patients with compensated cirrhosis, HVPG is a predictor of HCC independent of the duration and severity of cirrhosis 1.0 Probability of developing hepatocellular carcinoma (HCC) Log rank test: P=0.001 Hazard Ratio 6.0 ( ) 0.4 Baseline HVPG 10mmHg 0.2 Baseline HVPG <10mmHg Ripoll et al J Hepatology months

38 HVPG and surgical resection of HCC HVPG predicts the risk of hepatic decompensation and survival in Child A cirrhotic patients Bruix J, Gastroenterology 1996 Llovet JM, Hepatology 1999

39 FibroScan and severity of cirrhosis kpa No EV stage 2/3 No Child-Pugh B or C No past history of ascites No hepatocellular carcinoma No variceal bleeding EV: esophageal varices Foucher J, et al. Gut 2006;55:403 8

40 Sopravvivenza e stadio della fibrosi valutata mediante Fibroscan 1025 pazienti con ECA HCV+ seguiti prospetticamente, ripetono un Fibroscan dopo 3 anni (Mediana FU: 38 mesi) Sopravvivenza a 3 anni Fibroscan 7 kpa 99% Fibroscan >7- <14 kpa 96% Fibroscan > 14 kpa 77% J Vergniol ;Hepatol 2014

41 Sopravvivenza e stadio della fibrosi valutata mediante Fibroscan J Vergniol ; Hepatol 2014

42 Staging chronic hepatitis C in seven categories using fibrosis marker (FibroTest) and Transient elastography (Fibroscan) (Poynard et al J Hepatol 2014 ; vol 60 n 4: )

43 TE performance for prediction of first severe complications Severe complicance defining stage F4.3 TE predetermined cut off for stages Primary liver cancer Death F0 0 5 kpa 1.6% 0 % 3.7% F1>5 7.1 kpa 5.0% 1.1% 4.2% F2> kpa 11 % 2.1% 3.5% F3> kpa 25.7% 24.6% 11.8% F4.1 > kpa 23.4% 12.7% 20.3% F4.2>20 55 kpa 55.9% 33.6% 30.3% F4.3>50-75 kpa 71 % 58.7% 14.8% Poynard et al J Hepatol 2014 ; vol 60 n 4:

44 Survival without liver complications according baseline TE cc

45 Fibrotest performance for the prediction of complications Severe complicance defining stage F4.3 FT predetermined cut off for stages Primary liver cancer Death F % 0% 2.8% F1> % 0.9% 5.6% F2> % 1.5% 5.8% F3> % 12% 16.9% F4.1 > % 16.8% 14.4% F4.2> % 26.1% 29.1% F4.3> % 30.8% 53.1% Poynard et al J Hepatol 2014 ; vol 60 n 4:

46 Survival without liver complications according baseline FT

47 Grazie per l attenzione