Non-alcoholic fatty liver disease (NAFLD): ‘een vet probleem’ A.G. (Onno) Holleboom, endocrinoloog; per 31-12 vasc gnk, Vasculaire Geneeskunde | 14-05- ’19
Disclosures Sponsor / grant Gilead research Scholar award 2019(1) • • Honorarium Gilead NAFLD round table meeting Nederland-België 2019(1) • •
NAFLD-NASH: a disease spectrum
Hardy, Anstee, Ann Rev Pathol 2016
NASH: coined in 1981
NAFLD-NASH field in 2019 :
NAFLD-NASH: prevalence and burden • Increase in obesity, type 2 diabetes mellitus, ageing population • US: 64 million have NAFLD, medical cost $103 billion. - NASH-related cirrhosis: primary indication for liver Tx since 2018 • Europe-4: (Germany, France, Italy, UK): 52 million have NAFLD • annual cost €35 billion Younossi, Hepatology 2016; Paris NASH meeting 2018 • China: Unexpected Rapid Increase in the Burden of NAFLD in China From 2008 to 2018 • 2,054,554: 29,2% Zhou et al, Hepatology. 2019 May 9 • Modelling of the epidemic: exponential increase in disease burden Estes, Hepatology 2018
Worldwide estimated prevalence of NAFLD Rotterdam study - 3,041 participants general population > 45 years: transient elastography: significant liver fibrosis in 5.6% Younossi, Z. et al., Nat. Rev. Gastroenterol. Hepatol. 2017 Koehler et al, Hepatology 2016
NAFLD-NASH: hepatic component of MetSy 75% of DM2 has NAFLD 50% of hypertensives has NAFLD → mixed hyperlipidemia
NAFLD: driven by IR LXR, FAS Continuous NEFA flux, independent of feeding – metabolic inflexibility Hardy, Anstee, Isokuortti, Diabetologia 2017 Ann Rev Pathol 2016, after Donnelly, JCI 2015
NAFLD-NASH: major asCVD 75% of DM2 has NAFLD 50% of hypertensives has NAFLD → mixed hyperlipidemia ‘Two sides of the same Targer, NEJM 2010 Friedman, Nature Medicine 2018, dysmetabolic medal’ Stols-Goncalves, Holleboom, Nieuwdorp, Hovingh, Trends in Endocrinology in press 2019
NAFLD-NASH: major asCVD - Meta-analysis Wu et al, Sci Rep 2016: 164,494 participants, 21 cross-sectional studies, and 13 cohort studies) 75% of DM2 has NAFLD HR 1.9 - 2.3 n = 164,494 50% of hypertensives has NAFLD - Meta-analysis Stepanova & Younossi, Clin Gastr Hepatol 2012: → mixed hyperlipidemia NHANES-III, 11,500 participants, mean follow-up 171 months: asCVD most prevalent cause of death in patients with NAFLD: 5.62% Incident and prevalent asCVD higher in ‘Two sides of the same Targer, NEJM 2010 NAFLD patients, even after adjustments, Friedman, Nature Medicine 2018, dysmetabolic medal’ ORs 1-3 – 1.4 – 2.0 Stols-Goncalves, Holleboom, Nieuwdorp, Hovingh, Trends in Endocrinology in press 2019 - Multiple CAC studies, cIMT studies, a.o. Framingham Heart Study: congruent
NAFLD-NASH: major asCVD → mechanism? In my view: atherogenic, mixed dyslipidemia – hypersecretion of VLDL Liver has 4 protective mechanisms against lipid overload in NAFLD - Storage in lipid droplets - Mitochondrial beta-oxidation - Lysosomal degradation of lipid droplets / FFAs: lipophagy - Secretion of TG-rich apoB particles – VLDL Support from Mendelian randomization studies (Romeo Gothenburg; CCHS group Copenhagen): - PNPLA3, pure lipid droplet gene, no effect on VLDL. --> SNP: more NASH progression, not VLDL → not asCVD - TM6SF2, VLDL secretion gene, SNP: --> more NASH, reduced VLDL secretion, less asCVD Ergo: - NAFLD and asCVD: two sides of the same dyslipidemic medal? - NAFLD misnomer? Cardiometabolic liver disease?
Our view on NAFLD-NASH 1. Current clinical practice falls short is improving 2. Distinction between NAFL and NASH 3. Pathophysiology & drug targets 4. NAFLD-NASH in AUMC - Patient care - ANCHOR study: Amsterdam NAFLD NASH cohort
1. Patient care in NAFLD-NASH: why do we need to improve? Case finding Few outpatient clinics in NL Few validated Scepsis non-invasive tests No Dutch guideline Tushuizen, Holleboom , …, Blokzijl, Koek Capita Selecta NTVG , in revision No approved treatment; many trails and compounds underway Need for detection of early cases to prevent fibrosis/cirrhosis/asCVD
Case 1: mr. Y ., ~50 years, Dutch descent Algemene vasculaire spreekuur: Other causes such as alcohol, viral hepatitis and hemochromatosis: CVRM, secundaire preventie na OWI 2012 excluded Worsening DM2, BMI 35 No biopsy due to anticoagulant use C/ NASH-related cirrhosis, CPA 𝝳 -GT 67 U/l (0-40) ALAT 85 U/l (0 – 34) B/ initiated liraglutide for his worsening DM Fibroscan elastography: LSM: 17 kPa (<7) CAP: 354 dB/m
Case 2: mr. C, 62 years, Dutch descent • DM2 since 1999, poorly controlled despite insulin and oral medication • Former technical worker; osteoarthritis • BMI 32 • Diabetic foot ulcers, polyneuropathy • Fibroscan: LSM 24 kPa
Case 3: ms. O., 58 years, Indian descent Recently hypertensie-poli: malaise despite well controlled hypertension Other causes such as viral hepatitis and & DM2 hemochromatosis: excluded Biopsy: NASH-related cirrhoses Alkaline phosphatase 128 (40 - 120 U/L), gamma-GT 504 U/l (0-40), ASAT 83 U/l (0- → 1992 evaluation including biopsy 40), ALAT 79 U/l (0 – 34) OLVG-O – prolonged course Ultrasound of liver: → Need for earlier detection and management Coarse parenchyma, uneven contours, prominent caudate lobe, → We see the target population for early maximal diameter 12 cm (15). management, not the hepatologists Reduced hepatopetal flow in portal vein: 6-8 cm/s (20-40) → Pure endocrinologists don’t care about MetSy? Fibroscan: 75 kPa (<7)
Involved in NAFLD-NASH Vascular Medicine Diabetes nurses GPs Sumida et al, NASH therapies, J Gastro-enterol 2018
2. Distinction NAFL-NASH
2016 Fibrosis-4 score, Fib-4: ( Age x AST ) / ( Plts x ( sqr ( ALT ) ) Shah et al, Clin Gastro Hepatol 2009
Fibroscan ultrasound transient elastography: liver stiffness measurement Validated values for fibrosis staging: F0-F1 F2 F3 F4 ≤7.0 ≥7.5 ≤10 ≥14.0 kPa Fibroscan, 2 nd measure: steatosis, with controlled attenuation parameter (CAP , dB/m) Eddowes, Gastroenterology 2019(1)
Eddowes et al, Gastroenterology 2019(1): first prospective validation of Fibroscan - transient elastography
Liver biopsy - activity
Liver biopsy - fibrosis
3. NAFLD: Pathophysiology & drug targets Dongiovanni & Anstee, Curr Pharm Des 2013 Arab & Trauner, Annu Rev Pathol 2018
Insulin resistance GLP1 agonists Phase 2 LEAN trial with liraglutide: - Reduction in NASH and fibrosis - n = 22, vs 23 placebo Armstrong et al, Lancet 2016 ________________ Phase 2b – SEMANASH, semaglutide: underway
Insulin resistance & lipotoxicity PPARγ agonists: pioglitazone Phase 2 RCT , Cusi et al, Ann Int Med 2016 - 36 months - 168 patients with biopsy proven NASH and (pre)DM: Positive trial - no increase in AE - reproduced - phase 3 = ? Could consider pioglitazone, perhaps periodic treatments?
Lipotoxicity ACC inhibitor GS-0976 increase FFA beta oxidation by inhibiting enzymes of DNL Side effect: HTG via SREBP1 upregulation VLDL- packing, only in some patients (who already had hyperTG) Phase 2, 127 patients, Loomba Gastroenterology ’18
Lipotoxicity Selective thyromimetics Madrigal MGL-3196, Phase 2 positive halfway analysis, presented at EASL 2018 Diodenases are down in NASH: liver is in a state of hypothyroidism, Bohinc JCEM 2016 Positive effect on lipid profile: LDL down, Lp(a) strongy down, apoB and TG down May work via increase in lipophagy
Oxidative stress FFAs and other lipids (LPC?) disrupt membranes, leading to necroinflammation Vitamin E – PIVENS trial Sanyal et al NEJM 2010, vs pio and placebo 800 mg/day No overt DM Histologic improvement NASH No data on fibrosis Long-term safety? (prostatic cancer) Guideline: not firmly recommended
Bile acid receptors FXR agonists: obeticholic acid Flint study Phase 2b, stopped early for efficacy: reduction in NASH fibrosis. Also: reduced bacterial translocation (occludines), reduced portal hypertension Yet: LDL rose by 0.5 mmol/l Neuschwander-Petri et al, Lancet 2015 Phase 3 REGENERATE: significant, yet minute effect Also: FGF-19 and -21 analogues
Apoptosis ASK1-inhibitor: selonsertib Phase 2: positive, reduced fibrosis Loomba, Hepatology 2018 Phase 3 STELLAR3 for F3, STELLAR4 for cirrhosis, results presented @ ILC 2019(3): negative!
Inflammation and fibrogenesis Cenocriviroc CCR2/5 antagonist, reduces macrophage recruitment into adipose tissue Centaur phase 2b trial, positive Friedman, Ratziu Hepatology 2018 Currently in Phase 3, AURORA trial
Gut microbiome SIBO: Proteobacteria drive NAFLD-NASH Gut permeability increased in NAFLD- NASH Butyrogenics may protect - anti-inflammatory -reduced fatty acid synthase in murine model FMT trial, manuscript in preparation (Smits, Witjes, Nieuwdorp) For review: Koopman, Molinaro, Nieuwdorp, Holleboom, Aliment Pharm Ther, accepted 2019
Clinical practice in the near future: combination of therapies for this multifactorial disease • As for diabetes / MetSy / hypertension / dyslipidemia • Gilead’s ATLAS trial (ASK1 -i; FXRa) Also awaited: CVOTs, as for antidiabetics
Current management – recommendations and considerations • Diet (caloric restriction, coffee++, alcohol --), exercise • Weight loss 7-10%; glucose control; CVRM • GLP1-agonists, pioglitazone, vitamin E • Bariatric surgery
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