NAFLD/NASHの最近の動向 - NCGM

1 NAFLD/NASH 2020 1 24 2 Syndrome X Deadly quartet 1988 Reaven 1989 Kaplan 1991 DeFronzo 1987 (Matsuzawa) (WHO, 1998) NCEP-ATPIII 2001 1. 102 cm 88 cm 2. 150 mg/dL 3. HDL- 40 mg/dL 50 mg/dL 4. 130/85 mmHg 5. 110 mg/dL 85cm 90cm 150mg/dL 40mg/dL 130mmHg 85mmHg 110mg/dL ( ) HDL( ) 94 (4) : 794-809, 2005 1. A, B, C) 2. B, C) 3. B, C) 4. B, C) 5. 6. - - - - CoA TCA GLUT2 GK G-6-Pase GS PLa Phospho- glucomutase FFA FFA CD36 FFA influx TG VLDL MTTP TG excretion Acyl-CoA ACOX1 -oxidation SREBP-1c lipogenesis Acetyl-CoA Fatty acid Synthase PPAR , 2007.

2 104: 492-500 24 44126 40 0 20 10 30 n=26597 n=17529 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 ( ) NASH: Non-Alcoholic SteatoHepatitis NASH 3 2 2030 1 NAFLD NASH NAFLD : nonalcoholic fatty liver disease) NASH : (nonalcoholic steatohepatitis) NAFL : nonalcoholic fatty liver- ) NAFL NAFLD 11,714 5,811 5,903 NAFLD 32% 9% NAFLD 85% 87% (Hamaguchi M, et al, World J Gastroenterol 18:1508-16, 2012) 2020 4 2014 NAFLD/NASH 2014 2018 AASLD NAFLD 21 drinks/ 14 drinks/ AGA/AASLD 1 drink 10g 2 ALDH2 (aldehyde dehydrogenase 2) NAFLD NAFLD/NASH 2014 NAFLD (5 studies) (Dulai PS, et al.

3 Hepatology 2017) NAFLD/NASH 2007 NAFLD/NASH R 2011 10 Vs Stiffness E =3rVs2 r NASH ARFI Accoustic Radiation Force Impulse MRI / MRE MR NAFLD/NASH 2014 Transient elastography ) (mm/ms) (Kpa) (mm) (ms) 0 20 40 60 10 20 30 40 50 60 z t Young's modulus t z V S = 2 3r S V E = C (Ziol, et al. Hepatology 41:48-54, 2005 ) 0 10 20 30 40 50 (n=42) (n=120) NAFLD (KPa) 0 10 20 30 40 50 (n=42) (n=120) NAFLD 24 (KPa) 0 10 20 30 40 50 (n=42) (n=120) 24 Biopsy NASH Biopsy FL NAFLD (KPa) 0 10 20 30 40 50 (n=3) (n=21) NAFLD NASH (KPa) 0 10 20 30 40 (KPa) NAFLD F0 F1 F2 F3 F4 ( yoneda M, et al.

4 GUT 56: 1330-1331, 2007 ) BMI AUROC yoneda 2007 97 52 Stage 2 88 74 1 Stage 3 85 81 Obara 2008 17 50 Stage 2 9 100 93 2 Stage 3 11 75 93 Nobili 2008 50 13 26 Stage 2 100 92 3 Stage 3 1 100 100 Chang 2008 19 53 25 Stage 2 7 79 76 4 Stage 3 84 83 Wong 2010 246 51 28 Stage 2 91 76 5 Stage 3 100 95 Stage 2 7 79 76 Stage 3 94 95 NASH NAFLD/NASH 2014 (Imajyo K, et al. Gastroenterology 2016) MR elastography (MRE) Fibrosis Stiffness (KPa) 95 % CI Control + Stage 0 + Stage 1 + Stage 2 + Stage 3 + Stage 4 + MRE (KPa) Fibrosis Stiffness (KPa) 95 % CI Control + Stage 0 + Stage 1 + Stage 2 + Stage 3 + Stage 4 + MRE(n=142) (n=127) (Imajyo K, et al.

5 Gastroenterology 2016) MRI-PDFF 5 CLDQ Chronic Liver Disease Questionnaire QOL 7 NASH NAFLD activity score NAS 261 10 5 7 10 30 18 10 NAFLD/NASH NAFLD/NASH 2014 E NASH 2010 E 3 96 RCT E NASH 2015 E NAFLD/NASH propensive score UDCA RCT E NAFLD E NASH NAFLD/NASH NAFLD/NASH 2014 TGF- 1

6 P< p< 0 10 20 30 40 50 9 5 NS 10 4 37 5 NASH TGF- 1 TGF- 1 (ng/mL) Gastroenterology 110: A1205, 1996 Aliment Pharmacol Ther 15:1667-72, 2001 Hepatology 39:568-569, 2004 *: p< (vs ALT E * * Diet ALT (IU/L) 0 40 80 120 160 200 NASH * Gastroenterology 110: A1205, 1996 Aliment Pharmacol Ther 15:1667-72, 2001 Hepatology 39:568-569, 2004 Gastroenterology 110: A1205, 1996 Aliment Pharmacol Ther 15:1667-72, 2001 Hepatology 39:568-569, 2004 TZD RCT 2010 E 3 96 RCT E NASH 2 NASH NAFLD/NASH 2014 NAFLD RCT HMG-CoA RCT NASH 1 2015 2016 NASH NAFLD/NASH 2014 2015 RCT Takeshita Loomba NAFLD/NASH HMG-CoA NAFLD/NASH NAFLD/NASH)

7 C NAFLD/NASH 2014 2004 NASH ARB 2009 telmisaltan valsaltan RCT RCT ARB NASH 2011 2016 losartan telmisartan RCT ACE enalapril Cross-Sectional Study enalapril NASH Cross-Sectional Study 2014 2016 ARB ACE NASH NAFLD/NASH ACE ARB NAFLD/NASH 2014 AT1-receptor TGF- 1 II (Yokohama S, yoneda M, et 40:1222-1225, 2004) 20 40 60 80 100 120 12 48 24 0 * p< vs * * * ALT * * AST * -GTP * (IU/L) II NASH 1 1 1 2 1 2 1 1 2 1 3 2 1 1 1 4 2 1 3 2 5 2 1 3 2 6 3 2 4 4 7 2 1 3 3 (Yokohama, yoneda , et 40.)

8 1222-1225, 2004) * NAFLD NASH ** (1) BMI>37 (2)BMI>32 2 ** E ** ** NAFLD/NASH NAFLD NAFLD/NASH E ** 2 ( ) II NASH NAFL -7% ** * ** -7 10% (-7% ) (-7 10% ) NAFLD/NASH 2014 NASH (Neuschwander-Terti BA, Gastroenterology & Hepatology 14:589, 2018) NASH FXR agonist, Obeticholic acid (FLINT study) (25mg/day) 72 200 61 vs. 38 p 53 vs. 35 p 35 vs. 19 p 46 vs. 31 p (Lancet 385(9972):956-65, 2015) 2018 2 15 GLP-1 agonist (Liraglutide) Hepatocytes PPAR PPAR Phase II study Lancet.

9 2016 Feb 13;387(10019):679-90. doi (Lancet. 2016 Feb 13;387(10019):679-90. Liraglutide NASH LEAN Study ALT -GTP Semaglutide sc Semaglutide sc placebo sc RCT 72wk 0wk Treatment period (n=93) (n=372) LB (1) LB (2) Primary outcome: NASH resolution w/o worsening of fibrosis Semaglutide (Novo Nordisk, phase 2) NCT02970942 Semaglutide sc (n=93) (n=93) (n=93) 50 NASH ASK1 (Selonsertib) NASH ASK1 (Selonsertib) % Selonsertib (Loomba R, et al. Hepatology 67(2):549-559, 2018) (Zeka, Microbiol Mol Biol Rev 80; 793, 2016) ASK JNK F1 F2 F3 F4 Elafibranor EU) OCA Selonsertib Cenicriviroc JNK Emricasan GIP/GLP1 FGF-21 Targeted stage Drug name Semaglutide t p< ** p< ** p< p< ## p< vs 0W 180 170 160 150 140 130 120 110 100 mg/dL 24W 12W 4W 0W ## # 8 7 6 % HbA1c ** ** * 24W 12W 4W 0W 32 30 28 26 24 22 kg/m2 ** ** ** 24W 12W 4W 0W BMI n=39 n=39 n=39 (Sumida Y, yoneda M, et al.)

10 , Hepatol Res 49:64-71, 2019) SGLT2 ) NAFLD LEAD Study MRI-HFF: MRI HFF(hepatic fat fraction MRI-HFF ( ) n=39 n=39 35 30 25 20 15 10 5 0 0W 24W * t *p< vs 0W SGLT2 ) NAFLD LEAD Study (Sumida Y, yoneda M, et al., Hepatol Res 49:64-71, 2019) t *p< #p< ##p< vs 0W 70 60 50 40 30 20 10 0 IU/L AST 24W 12W 4W 0W * ## 90 80 70 60 50 40 30 20 10 0 ALT 24W 12W 4W 0W * ## 180 160 140 120 100 80 60 40 20 0 -GTP 24W 12W 4W 0W # ## IU/L IU/L n=39 n=39 n=39 SGLT2 ) NAFLD LEAD Study (Sumida Y, yoneda M, et al., Hepatol Res 49:64-71, 2019) NASH GLP-1 DPP4 NAFLD/NASH Clinical Question NAFLD/NASH sodium glucose cotransporter 2 (SGLT2) * NAFLD NASH ** (1) BMI>35 (2)BMI>32 2 ** E ** ** NAFLD/NASH NAFLD NAFLD/NASH 2020 ) E ** 2 ( ) GLP-1 SGLT2 ARB ACE NASH 7 ** * ** SPPARM 1 PPAR / 2 TG HDL-C A1 FGF21 3 ALT/ -GTP ( ) ( ) ( )