WORKSHOP. How to manage patients with NASH? Pr Jérôme Boursier Angers, France

Transcription

1 WORKSHOP How to manage patients with NASH? Pr Jérôme Boursier Angers, France 11th Paris Hepatology Conference January 16th, 2018

2 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) Medical ALT Medicalhistory history:: ALT::29 29IU/L, IU/L,AST AST::41 41IU/L IU/L -- Arterial GGT: Arterialhypertension hypertension GGT: IU/L, IU/L,ALP: ALP: IU/L IU/L -- Dyslipidemia Negative Dyslipidemia NegativeHCV HCVand andhbv HBVantibodies antibodies -- T2DM at 46 years old Ferritin: T2DM at 46 years old Ferritin: µg/L, µg/l,transferrin transferrinsat: sat: -- Alcohol 27% Alcohol::one onebottle bottleof ofwine wine/day, /day, 27% stopped since T2DM diagnosis stopped since T2DM diagnosis Glycemia: Glycemia:6,9 6,9mmol/l, mmol/l,hba1c: HbA1c:6,4% 6,4% HDL HDLchol: chol:1,18 1,18mmol/L mmol/l(46 (46mg/dL) mg/dl) Treatment: Treatment:valsartan, valsartan,amlodipine, amlodipine, Triglycerides: 1,10 mmol/l (96 Triglycerides: 1,10 mmol/l (96 pravastatine, metformine, insulin pravastatine, metformine, insulin mg/dl) mg/dl) Weight Prothrombin Weight99 99kg, kg,height height cm, cm,bmi BMI Prothrombintime: time:80% 80% 37 Platelets: 37 Platelets: G/L G/L Waist circumference 128 cm Albumin: Waist circumference 128 cm Albumin:42,8 42,8g/L g/l Arterial pressure 130/70 mm Hg Arterial pressure 130/70 mm Hg Doppler-US: Doppler-US: -- Bright Clinical Brightliver liver Clinicalexamination examination::nothing nothing relevant - Spleen Spleendiameter diameter mm mm relevant

3 Question #1 At At first first sight, sight, what what would would be be your your diagnosis diagnosis of of liver liver fibrosis fibrosis?? No-mild No-mild (F0-1) (F0-1) Significant Significant (F (F 2) 2) Advanced Advanced (F (F 3) 3) Cirrhosis Cirrhosis (F4) (F4) Unknown Unknown

4 NAFLD fibrosis score NAFLD fibrosis score 0,037 0,037 ** age age ++ 0,094 0,094 ** BMI BMI ++ 1,13 1,13 ** IFG/diabetes IFG/diabetes ++ 0,99 0,99 ** AST/ALT AST/ALT 0,013 0,013 ** platelets platelets ** albumin albumin ++ 1,675 1,675 Angulo, Hepatology 2007; Boursier, Current Opin Med Diag 2012; Shah, Clin Gastroenterol Hepatol 2009

5 NAFLD fibrosis score F0-2 F3/4 30% 30% AUROC 0,7 0,8 0,8 91.8% 91.8% 66.9% 66.9% Xiao, Hepatology 2017

6 NFS: a good fibrosis test in diabetics? 0,037*age 0,037*age ++ 0,094*BMI 0,094*BMI probable NASH 1,13*IFG/diabete 1,13*IFG/diabete (AST or ALT 30 (M) ou 19 (W),+T2DM, + 0,99*AST/ALT 0,99*AST/ALT no other cause, no alcohol) 0,013*platelets 0,013*platelets 0.66*albumin 0.66*albumin ++ 1,675 1, without NASH 1693 US diabetics (code ICD-9 from 09/11 to 11/15) Negative Intermediat e Positive Joshi, ILC2016-RS-4095

7 Question #2 Which Which method method would would you you use use in in you you daily daily clinical clinical practice practice to to evaluate evaluate liver liver fibrosis fibrosis in in this this patient patient?? FIB4 FIB Fibrotest Fibrotest // FibroMeter FibroMeter // ELF ELF Fibroscan Fibroscan ARFI ARFI // SSI SSI // ElastPQ ElastPQ MRE MRE Liver Liver biopsy biopsy

8 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) ALT M probe ALT::29 29IU/L, IU/L,AST AST::41 41IU/L IU/L GGT: - 10/18 valid measures GGT: IU/L, IU/L,ALP: ALP: IU/L IU/L Negative - 16,2 kpa (IQR: 8,0) NegativeHCV HCVand andhbv HBVantibodies antibodies Ferritin: - CAP: 289 db/m (IQR Ferritin: µg/L, µg/l,transferrin transferrinsat: sat: 27% 35) 27% XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3 kpa) - CAP: 275 db/m (IQR 38) Glycemia: Glycemia:6,9 6,9mmol/l, mmol/l,hba1c: HbA1c:6,4% 6,4% HDL HDLchol: chol:1,18 1,18mmol/L mmol/l(46 (46mg/dL) mg/dl) Triglycerides: Triglycerides:1,10 1,10mmol/L mmol/l(96 (96 mg/dl) mg/dl) Prothrombin Prothrombintime: time:80% 80% Platelets: Platelets: G/L G/L Albumin: Albumin:42,8 42,8g/L g/l Doppler-US: Doppler-US: -- Bright Brightliver liver -- Spleen Spleendiameter diameter mm mm

9 Question #3 What What is is your your diagnosis diagnosis of of liver liver fibrosis fibrosis?? No-mild No-mild (F0-1) (F0-1) Significant Significant (F (F 2) 2) Advanced Advanced (F (F 3) 3) Cirrhosis Cirrhosis (F4) (F4) Unknown Unknown

10 Factors influencing liver stiffness Steatosis De Ledinghen, Expert Med Rev Devices 2010 Boursier, J Gastroenterol 2014

11 Steatosis increases liver stiffness in NAFLD 33% 13% Petta, Hepatology 2016

12 Controlled Attenuation Parameter (CAP) Karlas, J Hepatol 2017

13 CAP to refine Fibroscan result in NAFLD CAP: < >340 < >340 Petta, Hepatology 2016

14 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) M probe ALT ALT::29 29IU/L, IU/L,AST AST::41 41IU/L IU/L - 10/18 valid GGT: GGT: IU/L, IU/L,ALP: ALP: IU/L IU/L measures Negative NegativeHCV HCVand andhbv HBVantibodies antibodies - 16,2 kpa (IQR: 8,0) Ferritin: Ferritin: µg/L, µg/l,transferrin transferrinsat: sat: - CAP: 289 db/m (IQR 27% 27% 35) XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3 kpa) - CAP: 275 db/m (IQR 38) Glycemia: Glycemia:6,9 6,9mmol/l, mmol/l,hba1c: HbA1c:6,4% 6,4% HDL HDLchol: chol:1,18 1,18mmol/L mmol/l(46 (46mg/dL) mg/dl) Triglycerides: Triglycerides:1,10 1,10mmol/L mmol/l(96 (96 mg/dl) mg/dl) Prothrombin Prothrombintime: time:80% 80% Platelets: Platelets: G/L G/L Albumin: Albumin:42,8 42,8g/L g/l Doppler-US: Doppler-US: -- Bright Brightliver liver -- Spleen Spleendiameter diameter mm mm

15 Fibroscan reliability criteria Boursier, Heaptology 2013

16 Fibroscan reliability criteria Liver stiffness <7,1 IQR/M 7,1-12,5 0,10 Very reliable 0,10 0,30 Reliable 0,30< 12,5 Poorly reliable Boursier, Heaptology 2013

17 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) ALT M probe ALT::29 29IU/L, IU/L,AST AST::41 41IU/L IU/L GGT: - 10/18 valid measures GGT: IU/L, IU/L,ALP: ALP: IU/L IU/L Negative - 16,2 kpa (IQR: 8,0) NegativeHCV HCVand andhbv HBVantibodies antibodies Ferritin: - CAP: 289 db/m (IQR Ferritin: µg/L, µg/l,transferrin transferrinsat: sat: 27% 35) 27% Indication of XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3 kpa) - CAP: 275 db/m (IQR 38) Glycemia: Glycemia:6,9 6,9mmol/l, mmol/l,hba1c: HbA1c:6,4% 6,4% HDL HDLchol: chol:1,18 1,18mmol/L mmol/l(46 (46mg/dL) mg/dl) Triglycerides: Triglycerides:1,10 1,10mmol/L mmol/l(96 (96 mg/dl) mg/dl) Prothrombin Prothrombintime: time:80% 80% Platelets: Platelets: G/L G/L Albumin: Albumin:42,8 42,8g/L g/l Doppler-US: Doppler-US: -- Bright Brightliver liver -- Spleen Spleendiameter diameter mm mm

18 Question #4 What What is is your your diagnosis diagnosis of of liver liver fibrosis fibrosis?? No-mild No-mild (F0-1) (F0-1) Significant Significant (F (F 2) 2) Advanced Advanced (F (F 3) 3) Cirrhosis Cirrhosis (F4) (F4) Unknown Unknown

19 Fibroscan XL probe

20

21 8,4 1,7 AUROC LSM failure (%) Fibroscan XL probe De Ledinghen, J Hepatol 2012

22 Fibroscan manufacturer recommendations M Mprobe probe ifif skin skin liver liver distance distance capsula capsula<25mm, <25mm, XL XLprobe probe ifif 25mm 25mm Manufacturer recommendatio ns Adjustment Boursier, AASLD 2017

23 Diagnostic target Cut-off value Studies Summar Summar Summar Summar (patients y Se y Spe y PPV y NPV ) Significant fibrosis 4,8 8,2 4 (654) 75,8 64,8 65,5 78,8 Advanced fibrosis 5,7 9,3 3 (579) 75,3 74,0 58,7 88,7 Cirrhosis 7,2 16,0 4 (654) 87,8 82,0 39,8 97,8

24 Fibrosis stage probability as a function of liver stiffness Boursier, J Hepatol 2016

25 Question #5 Would Would you you use use another another method method for for liver liver fibrosis fibrosis evaluation evaluation?? No No Fibrotest Fibrotest // FibroMeter FibroMeter // ELF ELF ARFI ARFI // SSI SSI // ElastPQ ElastPQ Elasto-MRE Elasto-MRE Liver Liver biopsy biopsy

26 Combination blood tests + Fibroscan F0-2 Fibroscan Fibroscan ++ NAFLD NAFLD fibrosis fibrosis score score F3/4 45% 45% FS < 7,9 kpa NFS < -1,455 Autres FS 9,6 kpa NFS > 0,676 F0/2 F0/2 Biopsy Biopsy F3/4 F3/4 96% 96% 100% 100% Petta, Liver Int 2015

27 Combination blood tests + Fibroscan Sensitivity Positive PV Biopsy Boursier, EASL 2017

28 Combination blood tests + Fibroscan Sensitivity Positive PV Biopsy Boursier, EASL 2017

29 Combination blood tests + Fibroscan Sensitivity Positive PV Biopsy Boursier, EASL 2017

30 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) ALT M probe ALT::29 29IU/L, IU/L,AST AST::41 41IU/L IU/L GGT: - 10/18 valid measures GGT: IU/L, IU/L,ALP: ALP: IU/L IU/L Negative - 16,2 kpa (IQR: 8,0) NegativeHCV HCVand andhbv HBVantibodies antibodies Ferritin: - CAP: 289 db/m (IQR Ferritin: µg/L, µg/l,transferrin transferrinsat: sat: 27% 35) 27% Indication of XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3,1) - CAP: 275 db/m (IQR 38) Glycemia: Glycemia:6,9 6,9mmol/l, mmol/l,hba1c: HbA1c:6,4% 6,4% HDL HDLchol: chol:1,18 1,18mmol/L mmol/l(46 (46mg/dL) mg/dl) Triglycerides: Triglycerides:1,10 1,10mmol/L mmol/l(96 (96 mg/dl) mg/dl) Prothrombin Prothrombintime: time:80% 80% Platelets: Platelets: G/L G/L Albumin: Albumin:42,8 42,8g/L g/l Doppler-US: Doppler-US: -- Bright Brightliver liver -- Spleen Spleendiameter diameter mm mm

31 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) M probe - 10/18 valid measures - 16,2 kpa (IQR: 8,0) - CAP: 289 db/m (IQR 35) Indication of XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3,1) - CAP: 275 db/m (IQR 38) Liver Liverbiopsy biopsy (NASH (NASHCRN CRNsystem) system) Steatosis Steatosis::<10% <10%of ofhepatocytes hepatocytes Lobular Lobularinflammation inflammation::11 Ballooning Ballooning::00 Portal Portalinflammation inflammation::00 Fibrosis Fibrosis::44

32 Question #6 What What is is your your final final diagnosis diagnosis?? NASH NASH cirrhosis cirrhosis Cryptogenic Cryptogenic cirrhosis cirrhosis Other Other

33 Cirrhosis: cryptogenic or not? UNOS data base, cryptogenic cirrhosis NASH cirrhosis alcoholic cirrhosis auto-immune cirrhosis Factors Factors associated associated with with NASH-cirrhosis NASH-cirrhosis - T2DM - Sex - Obesity - Caucasian - Age >60 Thuluvath, J Hepatol 2017

34 Patients (%) Cirrhosis: cryptogenic or not? NASH Cryptogenic Alcohol Auto-immune Thuluvath, J Hepatol 2017

35 Question #7 Would Would you you perform perform an an oesogastroduodenal oesogastroduodenal endoscopy endoscopy to to screen screen for for large large oesophageal oesophageal varices? varices? No No Yes Yes

36 LSM <20 kpa and Platelets >150 G/l

37 «Anticipate» normograms Albraldes, Hepatology 2016

38 Expanded Baveno criteria Baveno VI : LSM <20 kpa + platelets >150 G/l Anticipate Model : LSM + platelets (risk <5%) 3 cohorts Expanded Baveno VI : LSM <25 kpa + platelets >110 G/l 925 patients Patients (%) Baveno VI Anticipate model Expanded Baveno VI Augustin, Hepatology 2017

39 Expanded Baveno criteria Expanded criteria : LSM <25 kpa and platelets >110 G/L Patients (%) HCV (n=584) Alcohol (n=127) NASH (n=90) HBV (n=61) Augustin, Hepatology 2017

40 Question #8 Which Which specific specific treatment treatment for for the the liver liver would would you you consider? consider? Lifestyle Lifestyle modification modification Pharmacological Pharmacological treatment treatment Liver Liver transplantation transplantation Other Other

41 Lifestyle modification NASH resolution Improvement in NAS 2 points 10% % Weight loss (%) : 21/205 9/34 16/25 26/29 66/205 21/34 22/25 29/29 < < Vilar-Gomes, Gastroenterology 2015

42 NAFLD : treatment options Lifestyle modificatio n ««non non specific specific»» pharmacological pharmacological treatment treatment Antioxidant (vit E) Hepato-protective (UDCA) Anti-inflammatory (pentoxyfylline) Others (ARA2, PUFA ) Probiotics Antidiabetics : Glitazones, GLP1 agonist ««specific specific»» pharmacological pharmacological treatment treatment FXR Agonist PPAR α/δ Agonist ASK-1 inhibitors Cenicriviroc Others Endoscopic Endoscopic treatement treatement Endoscopic bypass Endoscopic sleeve Intragastric balloon Others

43 Results of studies in NASH cirrhotic patients Guidelines EASL 2016 : Drug therapy should be indicated for progressive NASH (bridging fibrosis and cirrhosis) Cirrhotic patients in lifestyle and pharmacological studies : - Either excluded - Or very few patients included No strong data about the balance between efficacy and safety in this particular subgroup of patients Guidelines AASLD 2017 : Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in ( ) NASH cirrhosis or cryptogenic cirrhosis.

44 Other medications Causes of death in NAFLD Other Liver Cancer Cardiovascular Metformin Metformin :: -- Overall Overall mortality mortality -- Need Need for for liver liver transplantation transplantation -- Hepatocellular Hepatocellular carcinoma carcinoma -- glutaminase glutaminase activity activity and and hepatic hepatic encephalopathy encephalopathy Statins Statins :: -- Hepatocellular Hepatocellular carcinoma carcinoma -- Portal Portal hypertension hypertension -- Infection Infection

45 NAFLD : treatment options Lifestyle modificatio n ««non non specific specific»» pharmacological pharmacological treatment treatment Antioxidant (vit E) Hepato-protective (UDCA) Anti-inflammatory (pentoxyfylline) Others (ARA2, PUFA ) Probiotics Antidiabetics : Glitazones, GLP1 agonist ««specific specific»» pharmacological pharmacological treatment treatment FXR Agonist PPAR α/δ Agonist ASK-1 inhibitors Cenicriviroc Others Endoscopic Endoscopic treatement treatement Endoscopic bypass Endoscopic sleeve Intragastric balloon Others Bariatric surgery

46 Question #9 One One year year later, later, the the patient patient has has lost lost 44 kg kg (4%, (4%, BMI: BMI: kg/m2) kg/m2) There There is is no no sign sign of of liver liver decompensation decompensation The The liver liver function function is is stable, stable, as as the the Fibrocan Fibrocan result result (XL: (XL: 15,0 15,0 kpa) kpa) Would Would you you consider consider bariatric bariatric surgery surgery?? No No Yes Yes

47 Would you consider bariatric surgery? Pro - Improves overall survival when indicated - Potential for cirrhosis regression Cons - Arterial hypertension and T2DM are well controlled - No active liver disease (alcohol stopped, no NASH on liver biopsy) - No level 1 evidence in cirrhosis - Safety?

48 Long-term mortality after gastric bypass surgery Adams, New Engl J Med 2007

49 Bariatric surgery 82 NASH patients who underwent bariatric surgery Paired liver biopsy (during surgery and one year after) At one year: 85% NASH resolution, 47% fibrosis improvement Patients (%) NAS score Fibrosis stade Lassailly, Gastroenterology 2015

50 Indication for bariatric surgery in adults : BMI 40 kg/m2 BMI 35 kg/m2 with at least one of the following comorbidities (that can be improved by the intervention) - Arterial hypertension - OSAS - T2DM - NASH - Osteo-articular disorders

51 #9. Would you consider bariatric surgery? Pro - Improves overall survival when indicated - Potential for cirrhosis regression Cons - Arterial hypertension and T2DM are well controlled - No active liver disease (alcohol stopped, no NASH on liver biopsy) - No level 1 evidence for bariatric surgery in cirrhosis - Safety?

52 Bariatric surgery in cirrhosis In-hospital mortality (%) 21,1 16,3 0,3 0,9 1 2,2 Nationwide Inpatient Sample, No cirrhosis (n= ) Compensated cirrhosis (n=3 888) Decompensated cirrhosis (n=62) Mosk, Clin Gastroenterol Hepatol 2011

53 Bariatric surgery in cirrhosis Study sample Systematic review : 9 articles / 122 patients - All well compensated cirrhosis - Portal hypertension : 7/122 - Female: 61% - Mean age: 49,6 years - Mean BMI: 50,4 kg/m2 Adjustable gastric Biliopancreatic banding; 12%diversion; 12% 61-73% 61-73% Excess Excess weigth weigth loss loss Sleeve gastrectomy; 34% at at 11 year year 30 RYGB; 42% Jan, Obes Surg 2015

54 Bariatric surgery in cirrhosis All Rate of patients (%) RYGB Sleeve gastrectomy Biliopancreatic diversion Adjustable gastric banding Jan, Obes Surg 2015

55 Clinical case Man Man63 63years yearsold, old,referred referredby byhis hisdiabetologist diabetologistfor forhigh highnafld NAFLDfibrosis fibrosis score score(1,37) (1,37) M probe - 10/18 valid measures - 16,2 kpa (IQR: 8,0) - CAP: 289 db/m (IQR 35) Indication of XL probe - 10/10 valid measures - 14,5 kpa (IQR: 3,1) - CAP: 275 db/m (IQR 38) Liver Liverbiopsy biopsy (NASH (NASHCRN CRNsystem) system) Steatosis Steatosis::<10% <10%of ofhepatocytes hepatocytes Lobular Lobularinflammation inflammation::11 Ballooning Ballooning::00 Portal Portalinflammation inflammation::00 Fibrosis Fibrosis::44