NASH : Diagnosis and investigation. VII Workshop international, Curitiba, Brazil 29/08/2014

Transcription

1 NASH : Diagnosis and investigation VII Workshop international, Curitiba, Brazil 29/08/2014 Vlad Ratziu, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

2 Usual diagnostic circumstances for NAFLD LFTs + Ultrasound Cirrhosis X NASH Increased ferritin LFTs + Metabolic RF Metabolic RF + Normal ALT Key points : presence of steatosis (ultrasound, markers) presence of metabolic risk factors

3 NASH : when to think about it? Metabolic risk factors BMI > 25 kg/m² Waist circ 94/80 ou 102/88 Arterial HTN 135/85 mmhg Glycemia >6.1 mmol/l TG > 1.7 mmol/l HDLc < 1/1.3 mmol/l Ferritin 350 µg/ml Atheromatosis 1 st degree family history Altered LFTs Steatosis on ultrasound Cirrhosis diagnosis

4 Work-up in patients with NAFLD: a multiorgan approach NAFLD Extrahepatic comorbidities? Liver condition Type 2 diabetes Sleep apnea Hypertension, arterial Dyslipidemia Cofactors of fibrosis Pathological form Stage Prognosis

5 Severity of histologic injury Obstructive sleep apnea aggravating NASH Diurnal asthenia Sleepiness Attention problems Frequent waking-up Snoring Severity of chronic intermittent hypoxia Courtesy Aron-Wisnewsky, J Hepatol 2011

6 NAFLD Secondary Alcohol Drugs (amiodarone, metothrexate, tamoxifen, corticosteroids) A/hypo betalipoprotéinémia Chronic HCV (genotype 3) Maladie de Wilson Toxiques industriels Lipodystrophies Cholesteryl ester storage disease Microvesicular steatosis PRIMARY Coexistence other CLDs Positive definition Alcohol Metabolic Risk Factors

7 NAFLD and ALD can coexist and HCV and HBV and - NAFLD SHOULD NO LONGER BE A DIAGNOSIS OF EXCLUSION

8 Screening strategies I Diagnostic tools Metabolic RF LFTs ULN IU/L Lab variablity Steatosis IR surrogates : HOMA Dynamic tests Waist circumference Adipose tissue IR Lipid metabolism IR US, CT, MRI : if >20-30% not quantifiable

9 Screening strategies IV General population - NO Patients with IR (metabolic RF, PCOS, lipodystrophia) : Chronic liver disease Metabolic risk factors IR Stéatose Liver biopsy Bariatric surgery, cholecystectomy Liver biopsy

10 What to do... in clinical practice? Metabolic Risk Factors LFTs Ultrasound Abnormal LFTs Steatosis Liver specialist referral Eliminate other causes of CLD Assess potential for progression & fibrotic severity (decide LB) Initiate monitoring +/- therapy

11 NAFLD NAFL Steatosis alone or nonspecific inflammation STEATOHEPATITIS Hepatic cell injury + Inflammation Different clinical outcome

12 Histological diagnosis of NASH A TRIAD -Steatosis -Hepatic cell injury (ballooning) -Inflammation (lobular, portal) Preferential ZONE 3 distribution TO REMEMBER : Mallory bodies and PMN infiltrate not necessary for diagnosis NAS score not diagnostic Fibrosis not part of the diagnosis

13 Steatosis : 0, 1, 2, 3 Ballooning : 0, 1, 2 Inflammation : 0, 1, 2

14 Agreement for diagnosis before and after the use of FLIP algorithm Κ score Biopsy with full agreement between pathologists (%) Biopsy with agreement with reference diagnosis (%) 1 st group 2 nd group Baseline classification Algorithmic classification Baseline classification Algorithmic classification /40 (65%) 31/40 (77%) /40 (85%) 39/40 (97%) /40 (45%) 17/40 (42%) /40 (70%) 30/40 (75%)

15 FLIP algorithm for NAFLD classification

16 SAF score S(0,1,2,3) A (bal+lob inflam 0,1,2,3,4) F (0,1,2,3,4) S3A2F1 S1A3F4

17 Clinical validation of the FLIP algorithm and of the SAF score Nascimbeni F, ILC 2014

18 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

19 Screening strategies II non invasive prediction WHAT WHY HOW Fibrosis Steatohepatitis Steatosis Prognosis Cirrhosis surveillance Pharmacol treatment Prognosis Intensive counselling Pharmacol treatment Diagnosis (if > sensitive US) Early changes therapy Risk of metabolic complications Serum markers (FibroTest, FibroMeter, ELF, Angulo*) Elastometry* Serum markers (CK18*, NASHDiagnostics, NASHTest) Serum markers (SteatoTest*, FLI*, Kotronen index) Elastometry- CAP attenuation

20 Staging fibrosis with NFS, FIB-4, and others High (>92%) NPV for advanced fibrosis Useful in clinical practice for excluding advanced fibrosis ELF performed only marginally better than NFS Modest PPV liver biopsy still neessary McPherson, Gut 2010 Guha, Hepatology 2008

21 Non-invasive measurement of hepatic fibrosis SERUM MARKERS TRANSIENT ELASTOMETRY FibroTest ELF Panel Fibromètre NAFLD fibrosis score Fibrometer biopredictive.com Biols.fr 33

22 Prediction of advanced fibrosis by Fibroscan Wong, Hepatology 2010

23 Fibroscan M or XL? M XL Failure Unreliable 10-16% 33-50% 1-2% 25% 1.7 Kpa (+/-2.3) lower for XL Similar diagnostic performance M XL F 2 F Wong, Am J Gastro 2012 Myers, Hepatology 2012 F XL probe second line if M fails?

24 Short-term variability of elastometry measurements 531 paired liver stiffness measurements in 432 patients > 1 day and <1 year apart Nascimbeni F, Clin Gastro Hepatol in press

25 Short-term variability of elastometry measurements 531 paired liver stiffness measurements in 432 patients > 1 day and <1 year apart kpa Nascimbeni F, Clin Gastro Hepatol in press

26 New Imaging Methods for Fibrosis Assessment Fibroscan M and XL Real-time shear-wave elastography Acoustic radiation force imaging MR-Elastography

27 Recent progress in non-invasive assesment of liver injury Combination of techniques Prognostic value New markers

28 Castera, Angulo Nat Rev Gastro Hepatol 2013

29 Fibroscan + ELF Algorithm Crespo, J Hepatol 2012

30 TE and FibroTest predicts overall mortality HCV, N=1457 Vergniol, Gastroenterology 2011

31 NFS predicts mortality NAFLD, N=320 Angulo, Gastroenterology in press

32 FGF-21 in NAFLD Most interesting in predicting progression to NAFLD Baseline FGF21 and BMI independent predictors of NAFLD Li, J Hepatol 2013

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34 P3NP as a marker of both NASH and N=172 NAFLD patients fibrosis Tanwar, Hepatology 2013

35 Serum CK-18 for the diagnosis of NASH Feldstein, Hepatology 2009

36 AUROC of Plasma CK-18 Fragment Concentration for NASH or Fibrosis N=424 obese/overweight US subjects Limited sensitivity (58%) and NPV (49%) for the diagnosis of NASH Inadequate screening test for NASH Courtesy K Cusi, J Hepatol 2013 in press

37 When to perform liver biopsy on an individual basis? Metabolically stable? Attempt diet and lifestyle change Failure (s) previous attempts? Never tried No change Improvement weight, IR, ALT N Comorbidities Patient motivation Trials Fibrosis risk FT/FS (or clinical) +/+ +/- -/- MONITORING LB

38 Monitoring LFTs Fibrosis : Serum markers (FibroTest, ELF panel, Fibrometer) Elastometry Metabolic condition : Serum glucose, lipids, HBA1c HOMA Repeat liver biopsy?

39 Ongoing challenges Identification of the disease in patients exposed to NASH risk-factors Confident identification of NASH without biopsy Validation of non-invasive long-term follow-up Large mass-screening test for idetification of mild, non progressive disease Reproducible histological classification with prognostic value