NAFLD/NASH: Criteri diagnostici e prognostici

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1 Monotematica AISF Personalizzazione della Cura in Epatologia NAFLD/NASH: Criteri diagnostici e prognostici Pisa ottobre 2013 Elisabetta Bugianesi MD, PhD Division of Gastro-Hepatology, University of Turin, Italy.

2 NAFLD: POSSIBLE OUTCOMES Kotronen, Arterioscler Thromb Vasc Biol 2008

3 The Spectrum of NAFLD Fatty Liver NASH Cirrhosis Fat infiltration >5% with or without mild inflammation Steatosis + necro-inflammatory changes (ballooning degeneration, Mallory bodies, megamitochondria) and/or fibrosis

4 Making The Diagnosis 1. Abnormal LFTs Raised ALT (Usually ALT > AST in NAFLD/NASH) 2. History Features of the Metabolic Syndrome Alcohol Intake (<14/21 units/week) No known pre-existing liver disease 3. Investigations Aim to exclude other liver diseases: Negative HBV & HCV Serology Negative Auto-Antibodies (ANA, AMA, SMA, LKM1, ANCA) Negative Coeliac Serology Normal Immunoglubulins, Ferritin, A1AT, Cu 2+, etc.

5 History Physical examination Laboratory tests Family occurrence of NAFLD and/or components of the metabolic syndrome Alcohol consumption (< 20 g/day) Height (m) Weight (kg) Blood cell count, total proteins and serum protein electrophoresis, PT, PTT, total bilirubin, AST, ALT, GGT, ALP Lipid profile (total cholesterol, HDL-cholesterol, tryglicerides) Diet BMI (kg/m 2 ) Fasting glucose and insulin Physical activity Waist circumference Markers HBV, HCV Body weight changes overtime Arterial pressure Autoantibodies including Celiac disease Drugs Hirsutism (women) Serum iron, transferrin, ferritin Exposure to toxins and chemicals Changes of the menstrual cycle Enlarged liver Alpha 1-antitrypsin Copper, ceruloplasmin TSH

6 Liver blood tests & NAFLD NAFLD is the commonest diagnosis in patients with incidental abnormal LFTs (ALT/ALP/GGT) In secondary care (60-70%) Skelly 2001, Pendino 2005 In primary care (26%) Armstrong J Hepatol 2012 BUT: Most patients with NAFLD by MRS (~80-90 %) have normal LFTs Browning 2004, Wong 2013 Screening by USS in high risk groups? Not advised due to uncertainties over diagnostic tests and treatment options (according to AASLD/AGA/ACG Practice Guidelines Chalasani 2012)

7 Diagnosis of NAFLD Components of Metabolic Syndrome Insulin Resistance (HOMA-R, OGIS) Fatty Liver Index (Dyonisos) BMI, waist circumference, triglycerides and GGT with an accuracy of 0.84 (95%CI ) in detecting fatty liver. FLI > 60 PPV > 78%; FLI < 20 NPV > 91%. Imaging USS Sensitivity , PPV 62% Ruhl 2004 CT Sensitivity: 93%, PPV: 76% Saadeh 2002 USS, CT and NMR only sensitive when steatosis >33% 1 H-MRS sensitive to >5% but too expensive for routine use Browning 2004

8 Oral glucose tolerance test (OGTT) predicts Type 2 Diabetes HOMA-R: 3.5 (< 2.7) mg/dl mcui/ml Glucose min Insulin

9 Risk Stratification Predictors of progression: Age >45-50 Diabetes BMI >28-30 Hypertension IR severity fibrosis at LB

10 Blood tests predicting presenceof NASH Markers of apoptosis: CK-18 fragments Feldstein 2009 Ferritin Bugianesi 2004, Kowdley 2012

11 Clinical Scores for the prediction of fibrosis in NASH AST/ALT ratio AST/platelet ratio index (APRI) AST (IU/L)/ (ULN) /platelet count (x10 9 /L) x 100 Score > 1 associated with cirrhosis FIB-4 score age x AST (IU/L)/platelet count (x10 9 /L) x ALT (IU/L) Score < 1.3 to exclude advanced fibrosis; Score > 3.25 to diagnose advanced fibrosis NAFLD Fibrosis Score x Age (years) x BMI (kg/m2) x IFG/diabetes (yes = 1, no = 0) x AST/ALT ratio x platelet (x109/l) x Albumin (g/dl). Score < to exclude advanced fibrosis; Score > to diagnose advanced fibrosis Commercial Panels including ELF Test and Fibrotest As the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for a liver biopsy (AGA/AASLD guidelines) (Williams, Gastro 1988; Wai, Hepatology 2003; Harrison, Gut 2008; Vallet-Pachard, 2007; Bedogni, 2006)

12 Comparison of the Diagnostic Performance of the Tests for Advanced Fibrosis (F3/F4) Test Cut-off Sens (%) Spec (%) PPV (%) NPV (%) AST/ALT ratio APRI BARD score FIB-4 score NAFLD fibrosis score (McPherson, Gut 2010)

13 Non-invasive methods and prognosis Fatty liver index Independently associated with liver deaths at 15 yrs ELF Calori Hepatology 2011 Associated with 7 yr liver related mortality/morbidity Simple scores Parkes Gut 2010 (NFS, APRI, FIB-4, BAAR) Predict liver related morbidity, death and OLTx at 9 yrs Angulo et al Gastro 2013 NFS < NFS < to NFS > 0.676

14 Imaging in NASH 1. Fibroscan assessment of fibrosis measuring liver stiffness initial promising results in NAFLD Wong, Hepatology 2010 BUT further validation needed Failure Rate 25.5% if BMI 30 and 2.6% if BMI < 30 special XL probe for obese patients De Ledinghen, J Hepatol 2009 caution in NAFLD => results may be influenced by steatosis Gaia, J Hepatol CONTENTS 75 KPa F2 F3 F4 2. Acoustic radiation ARFI Palmeri Real time elastography Ochi 2012

15 NAFLD/NASH diagnosis & prognosis: summary Diagnosis of NAFLD currently relies on clinical features, blood tests, + USS For NASH and severity: AST/ALT ratio <0.8, Fibroscan <10, NAFLD score < excludes advanced fibrosis: NPV >90% Other patients still require liver biopsy for prognosis and treatment decisions Validated and clinically useful NASH/fibrosis markers with PPV >90% urgently needed Genotyping for risk stratification?

16 Thank you for your attention! Acknowledgements: Dr Ester Vanni Dr Lavinia Mezzabotta Dr Chiara Rosso Dr Marilena Abate Dr Silvia Carenzi Dr Elena Gentilcore Dr Alessandro Musso Prof Antonina Smedile Prof Mario Rizzetto