Non-alcoholic fatty liver disease (NAFLD): belang voor de internist Dr. A.G. (Onno) Holleboom, endocrinoloog; per 31-12 vasc gnk Vasculaire Geneeskunde Amsterdam UMC, locatie AMC
Disclosures A.G. Holleboom, Amsterdam UMC Sponsor / grant Gilead research Scholar award 2019(1) • • Honorarium Gilead NAFLD round table meeting Nederland-België 2019(1) • •
NAFLD: a disease spectrum Holleboom, …, Blokzijl, Koek, Tushuizen, Focus Vasculair sept. ‘19
NASH: coined in 1981
NAFLD field in 2019 :
NAFLD: hepatic component of MetSy 75% of DM2 has NAFLD, 50% of hypertensives has NAFLD Targer, NEJM 2010, Friedman, Nature Medicine 2018 Stols-Goncalves D, Hovingh GK, Nieuwdorp M, Holleboom AG, Trends in Endocrinology & Metabolism, Cell Press in press 2019
Elements metabolic syndrome: pharmacotherapy • Hypertension antihypertensives - ABCD • Type 2 diabetes mellitus oral antidiabetics, insulin, GLP1-a, SGLT2-i • Mixed dyslipidemia statins, fibrates, (PCSK9-i) • NAFLD no proven / approved treatment
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: major asCVD - Meta-analysis Wu et al, Sci Rep 2016: 164,494 participants, 21 cross-sectional studies, and 13 cohort studies) HR 1.9 - 2.3 - Meta-analysis Stepanova & Younossi, Clin Gastr Hepatol 2012: 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 Targer, NEJM 2010 NAFLD patients, even after adjustments, Friedman, Nature Medicine 2018, 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: 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: 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 • Modelling of the epidemic: exponential increase in disease burden Estes, Hepatology 2018
Worldwide estimated prevalence of NAFLD Lifelines cohort Groningen: 22% of 37,496 Rotterdam study - 3,041 participants general population > 45 years: participants (median age 44 years, 62.1% female), Fibroscan: significant liver fibrosis in 5.6% 8,259 (22.0%) had a Fatty Liver Index > 60 Younossi, Z. et al., Nat. Rev. Gastroenterol. Hepatol. 2017 E. Koehler, JHA Janssen, Hepatology 2016 Van den Berg, Blokzijl, PLoS One 2017
Patient care in NAFLD: where can we improve? Case finding Care path, collaboration Scepsis Validation non-invasive tests Need for detection of early cases to prevent fibrosis/cirrhosis/asCVD Tushuizen ME, Holleboom AG, … Koek GH, NTVG Stand van zaken, in press 2019 Focus Vasculair, sept 2019; Huisarts & Wetenschap, volgt
Distinction NAFL-NASH
Eddowes et al, Gastroenterology 2019(1): first prospective validation of Fibroscan - transient elastography
European 2016 multidisciplinary guideline
British practice Validation in 3,012 patients: - Detection of advanced fibrosis and cirrhosis: OR 5.18 - Reduction unnecessary referrals from primary care: 81% Srivastava, UCL, J Hepatol 2019(7) Byrne C et al, BMJ 2018 Dutch practice Tushuizen ME, Holleboom AG, … Koek GH, NTVG Stand van zaken, in press 2019 Focus Vasculair, in press 2019 ; Huisarts & Wetenschap, volgt Plan: richtlijn NVMDL – NIV – NVE – NVIVG – KNG - NHG (h.a. Jean Muris; module in DM2 en LFT standaard?) – ‘de lange weg ’. Inmiddels ingeslagen
Voorstel zorgpad NAFLD Holleboom, …, Blokzijl, Koek, Tushuizen, Focus Vasculair sept. ‘19
Care for NAFLD patients in Amsterdam UMC Since May 2018: outpatient NAFLD clinic Until targeted treatment becomes available: -- MetSy → NAFLD - Lifestyle management, dietician - -- fibroscan @ internal medicine - Treatment of diabetes - -- close collaboration with hepatologists, - CVRM GE pediatricians - Bariatric surgery - Surveillance for cirrhosis, HCC Per March 2019: Multidisciplinary outpatient clinic at VUmc Consider: Together with dr. Sandjai Ramsoekh, dietician, lifestyle coach - GLP1-agonist - Pioglitazone @ Internal medicine, endocrinology: - Vitamine E All DM2 patients - Treatment in trials - Retinopathy - Nefropathy - Neuropathy - Hepatopathy – NAFLD-NASH: screen: infrequently; with a low threshhold
Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) - NASH: complex pathogenesis - Major drug development effort Nature Outlook 2017(11)
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: significant reduction of NASH and fibrosis - versus hypocaloric diet alone - no increase in AE - phase 3 = ? Could consider pioglitazone, perhaps periodic treatments?
Lipotoxicity Elafibranor: PPAR alpha/delta agonist - Golden trial GenFit Phase 2B - Positive study, resolution of necro- inflammation and NASH - Currently in Phase 3 RESOLVE-IT , results expected Dec 2021
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 pioglitazone and placebo 800 mg/day No overt diabetes mellitus Histologic improvement NASH No data on fibrosis Long-term safety? (prostatic cancer) EASL-EASD-EASO guideline: not firmly recommended
Bile acid receptors FXR agonists: obeticholic acid Flint study Phase 2b, stopped early for efficacy: reduction in NASH fibrosis. FXR: reduced DNL, increased fatty acid oxidation Also: reduced bacterial translocation (occludines), reduced portal hypertension Yet: LDL rose by 0.5 mmol/l (LPL inhibition) Neuschwander-Petri et al, Lancet 2015 Phase 3 REGENERATE: significant, yet minute effect
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 N, Molinaro A, Nieuwdorp N, Holleboom AG, Aliment Pharm Ther, 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
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