Non-alcoholic steatohepatitis (NASH): Definition, natural history and current therapeutic interventions Frank Tacke University Hospital Aachen, Germany EMA Workshop on Liver Diseases London, Dec 3rd, 2018
Disclosures Frank Tacke • Research support (materials, funding): Tobira/Allergan, Galapagos, Inventiva, BMS • Speaker/Consulting: Tobira/Allergan, Gilead, AbbVie, BMS, Falk, Boehringer, Galapagos, Intercept, Inventiva
Non-alcoholic Fatty Liver Disease: The epidemiological challenge 20-30% NAFLD 3% NASH 0.2%-0.5% HCC Total (EU: ~116 M) (EU: ~10 M) (EU 200,000 – population 500,000) HEPAMAP. A roadmap for hepatology research in Europe: An overview for policy makers. EASL 2015 BMI (kg/m²) 1974 2014 mean BMI ♂ mean BMI ♂ 105 millions BMI>30 641 millions BMI>30 NCD Risk Factor Collaboration, Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet. 2016; 387(10026):1377-96
Non-alcoholic Fatty Liver Disease: The epidemiological challenge 20-30% NAFLD 3% NASH 0.2%-0.5% HCC Total (EU: ~116 M) (EU: ~10 M) (EU 200,000 – population 500,000) HEPAMAP. A roadmap for hepatology research in Europe: An overview for policy makers. EASL 2015 Projection for Germany 25.0 25.0 2016 2030 Millions Millions NASH 20.9 17.0 + 42% 20.0 20.0 NASH 18.4 15.9 15.0 15.0 NASH- Zirrhose NAFLD 10.0 10.0 x 2.5 5.0 1.6 5.0 1.2 1.1 0.8 0.7 0.4 0.5 0.2 0.0 0.0 Total F0 F1 F2 F3 F4 Total F0 F1 F2 F3 F4 Estes C, et al. J Hepatol. 2018; 69(4):896-904
Non-alcoholic Fatty Liver Disease: The epidemiological challenge 20-30% NAFLD 3% NASH 0.2%-0.5% HCC Total (EU: ~116 M) (EU: ~10 M) (EU 200,000 – population 500,000) HEPAMAP. A roadmap for hepatology research in Europe: An overview for policy makers. EASL 2015 Projection for UK 18.0 18.0 2016 16.9 2030 Millions Millions 13.8 NASH 16.0 16.0 14.1 + 43% 12.1 NASH 14.0 14.0 12.0 12.0 NASH- 10.0 10.0 Zirrhose 8.0 8.0 NAFLD x 2 6.0 6.0 4.0 4.0 1.2 0.9 0.8 2.0 2.0 0.6 0.5 0.3 0.4 0.2 0.0 0.0 Total F0 F1 F2 F3 F4 Total F0 F1 F2 F3 F4 Estes C, et al. J Hepatol. 2018; 69(4):896-904
Non-alcoholic Fatty Liver Disease: The clinical challenge • Old(er) age, high(er) body-mass index • Many comorbidities (diabetes, kidney, cardiovascular…) • Substantial proportion unaware of their liver condition • High(er) rate of malignancies
Non-alcoholic Fatty Liver Disease: The clinical challenge https://broadly.vice.com
Extrahepatic complications of non-alcoholic fatty liver disease Type 2 Diabetes Chronic Kidney Cardiovascular Disease Disease Colorectal NAFLD OSAS (Sleep Apnea) cancer PCOS (Polycystic Hypothyroidism Ovary Syndrome) Osteoporosis Byrne CD & Targher G, J Hepatol 2015; 62: S47–S64
Management of fatty liver disease: EASL multidisciplinary Clinical Practice Guideline • Chairs – EASL: Giulio Marchesini – EASD: Michael Roden – EASO: Roberto Vettor Panel members • – EASL: Christopher P Day, Jean-François Dufour, Ali Canbay, Valerio Nobili, Vlad Ratziu, Herbert Tilg – EASD: Amalia Gastaldelli, Hannele Yki-Järvinen, Fritz Schick – EASO: Gema Frühbeck, Lisbeth Mathus-Vliegen • Reviewers – Elisabetta Bugianesi, Helena Cortez-Pinto, Stephen Harrison EASL–EASD–EASO CPG NAFLD. J Hepatol 2016; 64:1388–402
Natural history of fatty liver disease: Definitions of NAFLD, NAFL and NASH NAFLD • Excessive hepatic fat accumulation with IR • Steatosis in >5% of hepatocytes* • Exclusion of secondary causes and AFLD † NAFL NASH HCC • Pure steatosis • Steatosis and mild lobular inflammation Early Fibrotic Cirrhotic ≥F 2 to ≥F 3 fibrosis F0/F1 fibrosis F4 fibrosis Definitive diagnosis of NASH requires a liver biopsy *According to histological analysis or proton density fat fraction or >5.6% by proton MRS or quantitative fat/water-selective MRI; † Daily alcohol consumption of ≥30 g for men and ≥20 g for women EASL–EASD–EASO CPG NAFLD. J Hepatol 2016; 64:1388–402
Diagnosis and staging of fatty liver disease: Role of liver biopsy • Liver biopsy is essential for the diagnosis of NASH – Clinical, biochemical or imaging measures cannot distinguish NASH from steatosis • NAFL encompasses – Steatosis alone plus ONE of lobular or portal inflammation OR ballooning • NASH requires – Steatosis AND – Lobular or portal inflammation AND – Ballooning • NAS scoring indicates disease severity* *Should not be used for initial diagnosis Recommendations Grade of evidence Grade of recommendation NASH has to be diagnosed by a liver biopsy showing steatosis, A 1 hepatocyte ballooning and lobular inflammation EASL–EASD–EASO CPG NAFLD. J Hepatol 2016; 64:1388–402
Diagnosis and staging of fatty liver disease: Role of liver biopsy NAFLD normal fibrosis NASH Courtesy of Dr. Thomas Ritz, Institute of Pathology, University Hospital Aachen
Natural history of fatty liver disease: Estimated progression rates NAFLD 12 − 40% NASH ~10% NASH-fibrosis (F3) NAFLD / NASH 30-50% NASH-cirrhosis NASH-fibrosis cirrhosis 0.25-3% HCC /year 0.3-2.6% /year 0.04-0.3% /year
Fibrosis determines the prognosis of non-alcoholic fatty liver disease • Meta-analysis of 5 studies on fibrosis-related mortality • 1,495 NAFLD patients with 17,452 patient years of follow-up Mortality rate by fibrosis stage Mortality rate ratio by fibrosis stage All Cause Liver Related All Cause Liver Related Mortality rate per 1,000 PYF 42.30 50 50 (3.51-510.34) 45 45 Mortality rate ratio 40 40 35 35 30 30 16.69 25 25 (2.92-95.36) 20 20 9.57 15 15 (1.67-54.93) 1.41 6.40 10 3.48 (0.17-11.95) (4.11-9.95) 10 (2.51-4.83) 1.58 2.52 5 5 (1.19-2.11) (1.85-3.42) 0 0 Stage 1 Stage 2 Stage 3 Stage 4 Stage 1 Stage 2 Stage 3 Stage 4 PYF, patients years of follow-up Mortality rate ratio = actual mortality versus expected mortality Dulai PS, et al. Hepatology 2017; 65: 1557–1565.
Fibrosis determines the prognosis of non-alcoholic fatty liver disease • 458 NAFLD patients (bridging fibrosis, F3, n=159; Child A5 cirrhosis, n=222; Child A6 cirrhosis, n=77); 4 tertiary centers, mean follow-up 5.5 years • Deaths: n=37, Liver Transplant: n=37, decompensation: n=88, Liver Cancer (HCC): n=41, Cardiovascular events: n=14, non-liver cancer: n=30 Vilar-Gomez E, et al. Gastroenterology . 2018; 155(2):443-457.
Fibrosis determines the prognosis of non-alcoholic fatty liver disease • 458 NAFLD patients (bridging fibrosis, F3, n=159; Child A5 cirrhosis, n=222; Child A6 cirrhosis, n=77); 4 tertiary centers, mean follow-up 5.5 years • Deaths: n=37, Liver Transplant: n=37, decompensation: n=88, Liver Cancer (HCC): n=41, Cardiovascular events: n=14, non-liver cancer: n=30 Vilar-Gomez E, et al. Gastroenterology . 2018; 155(2):443-457.
A potential algorithm for risk assessment in non- alcoholic fatty liver disease Hepatic steatosis on imaging ± elevated serum ALT levels Evaluate alcohol Confirm NAFLD Exclude alternate causes of ↑ALT levels consumption Low-risk profile Intermediate-risk profile High-risk profile BMI < 29.9 BMI > 29.9 ALT level > AST level Age < 40 yrs Age > 40 yrs Platelets < 150,000 Noninvasive fibrosis No T2DM or Multiple features of the estimation: metabolic syndrome metabolic syndrome Noninvasive fibrosis features • FIB-4 > 2.67 Noninvasive fibrosis estimation: • APRI > 1.5 estimation: • FIB-4 1.30-2.67 • NFS > 0.675 FibroScan > 11 kPa • FIB-4 < 1.30 • APRI 0.5-1.5 • APRI < 0.5 • NFS -1.455-0.675 FibroScan 6-11 kPa • NFS < -1.455 FibroScan < 5 kPa Consider liver biopsy or Follow and reassess as Consider liver biopsy confirmatory testing for risk factors evolve cirrhosis (eg, MRE) Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol . 2016; 13:196-205.
A potential algorithm for risk assessment in non- alcoholic fatty liver disease Hepatic steatosis on imaging ± elevated serum ALT levels Evaluate alcohol Confirm NAFLD Exclude alternate causes of ↑ALT levels consumption EASL-Guideline 2016: Low-risk profile Intermediate-risk profile High-risk profile Recommendation for liver biopsy, if BMI < 29.9 BMI > 29.9 ALT level > AST level NASH or fibrosis is suspected Age < 40 yrs Age > 40 yrs Platelets < 150,000 Noninvasive fibrosis No T2DM or Multiple features of the estimation: metabolic syndrome metabolic syndrome Noninvasive fibrosis features • FIB-4 > 2.67 Noninvasive fibrosis estimation: • APRI > 1.5 estimation: • FIB-4 1.30-2.67 • NFS > 0.675 FibroScan > 11 kPa • FIB-4 < 1.30 • APRI 0.5-1.5 • APRI < 0.5 • NFS -1.455-0.675 FibroScan 6-11 kPa • NFS < -1.455 FibroScan < 5 kPa Consider liver biopsy or Follow and reassess as Consider liver biopsy confirmatory testing for risk factors evolve cirrhosis (eg, MRE) Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol . 2016; 13:196-205.
Natural history of fatty liver disease: Estimated progression rates NAFLD / NASH NASH-fibrosis cirrhosis 0.25-3% HCC /year 0.3-2.6% /year 0.04-0.3% /year
Natural history of fatty liver disease: Progression and Regression NAFLD / NASH NASH-fibrosis cirrhosis 0.25-3% HCC /year 0.3-2.6% /year 0.04-0.3% /year
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