belang voor de internist Dr. A.G. (Onno) Holleboom, endocrinoloog; - - PowerPoint PPT Presentation

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belang voor de internist Dr. A.G. (Onno) Holleboom, endocrinoloog; - - PowerPoint PPT Presentation

Sep 19, 2023 211 likes •617 views

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

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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

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Disclosures A.G. Holleboom, Amsterdam UMC

  • Sponsor / grant
  • Gilead research Scholar award 2019(1)
  • Honorarium
  • Gilead NAFLD round table meeting Nederland-België 2019(1)
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Holleboom, …, Blokzijl, Koek, Tushuizen, Focus Vasculair sept. ‘19

NAFLD: a disease spectrum

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NASH: coined in 1981

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NAFLD field in 2019:

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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

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Elements metabolic syndrome: pharmacotherapy

  • Hypertension

antihypertensives - ABCD

  • Type 2 diabetes mellitus
  • ral antidiabetics, insulin, GLP1-a, SGLT2-i
  • Mixed dyslipidemia

statins, fibrates, (PCSK9-i)

  • NAFLD

no proven / approved treatment

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NAFLD: driven by IR

Hardy, Anstee, Ann Rev Pathol 2016, after Donnelly, JCI 2015 Continuous NEFA flux, independent of feeding – metabolic inflexibility LXR, FAS

Isokuortti, Diabetologia 2017

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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 NAFLD patients, even after adjustments, ORs 1-3 – 1.4 – 2.0

  • Multiple CAC studies, cIMT studies, a.o.

Framingham Heart Study: congruent

Targer, NEJM 2010 Friedman, Nature Medicine 2018, Stols-Goncalves, Holleboom, Nieuwdorp, Hovingh, Trends in Endocrinology in press 2019

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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?
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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

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Younossi, Z. et al., Nat. Rev. Gastroenterol. Hepatol. 2017

  • E. Koehler, JHA Janssen, Hepatology 2016

Van den Berg, Blokzijl, PLoS One 2017

Worldwide estimated prevalence of NAFLD

Rotterdam study - 3,041 participants general population > 45 years: Fibroscan: significant liver fibrosis in 5.6% Lifelines cohort Groningen: 22% of 37,496 participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a Fatty Liver Index > 60

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Patient care in NAFLD: where can we improve?

Validation non-invasive tests

Care path, collaboration

Need for detection of early cases to prevent fibrosis/cirrhosis/asCVD

Scepsis

Case finding

Tushuizen ME, Holleboom AG, … Koek GH, NTVG Stand van zaken, in press 2019 Focus Vasculair, sept 2019; Huisarts & Wetenschap, volgt

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Distinction NAFL-NASH

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Eddowes et al, Gastroenterology 2019(1): first prospective validation of Fibroscan - transient elastography

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2016

European multidisciplinary guideline

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Validation in 3,012 patients:

  • Detection of advanced fibrosis and

cirrhosis: OR 5.18

  • Reduction unnecessary referrals

from primary care: 81% 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

British practice

Srivastava, UCL, J Hepatol 2019(7)

Dutch practice

Byrne C et al, BMJ 2018

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Holleboom, …, Blokzijl, Koek, Tushuizen, Focus Vasculair sept. ‘19

Voorstel zorgpad NAFLD

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Since May 2018: outpatient NAFLD clinic

  • - MetSy → NAFLD
  • -- fibroscan @ internal medicine
  • -- close collaboration with hepatologists,

GE pediatricians Per March 2019: Multidisciplinary outpatient clinic at VUmc Together with dr. Sandjai Ramsoekh, dietician, lifestyle coach @ Internal medicine, endocrinology: All DM2 patients

  • Retinopathy
  • Nefropathy
  • Neuropathy
  • Hepatopathy – NAFLD-NASH:

screen: infrequently; with a low threshhold

Care for NAFLD patients in Amsterdam UMC

Until targeted treatment becomes available:

  • Lifestyle management, dietician
  • Treatment of diabetes
  • CVRM
  • Bariatric surgery
  • Surveillance for cirrhosis, HCC

Consider:

  • GLP1-agonist
  • Pioglitazone
  • Vitamine E
  • Treatment in trials
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  • NASH: complex pathogenesis
  • Major drug development effort

Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic steatohepatitis (NASH)

Nature Outlook 2017(11)

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NAFLD: Pathophysiology & drug targets

Arab & Trauner, Annu Rev Pathol 2018 Dongiovanni & Anstee, Curr Pharm Des 2013

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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

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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?

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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

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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

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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

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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

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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

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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!

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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

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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

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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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NAFLD research program at Amsterdam UMC

ANCHOR

  • Cohort study
  • 3 MD PhD students
  • 1 research nurse
  • AMC & VUmc

CRISTINA

  • Exercise intervention
  • Marie-Curie ITN

RCTs

  • GLP1 agonist - semaglutide (Ph2b)
  • VAP1 inhibitor (Ph2a, b)
  • Modified PPARj agonist (Ph3)
  • EU biobank study
  • 1 research nurse @ AMC

Cell and mouse models

  • turnover of hepatic lipid droplets
  • Amsterdam UMC Fellowship

BARNARD study

  • gut-derived probiotic
  • TKI-PPP grant

NILE

  • Helius multiethnic cohort Amsterdam
  • Prevalence data, genetic discovery
  • Validation NITs in other ethnicities
  • Gilead Research Scholar, NN

PRISMA VUmc

  • Lifestyle program, coaches
  • Group sessions
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Hardy, Anstee, Ann Rev Pathol 2016

  • Rationale

Deep phenotyping van:

  • Verschil steatose en NASH
  • Verschil rapid versus slow progressors

Doelen

  • Identificatie van biomarkers voor steatose, inflammatie en fibrose
  • Identificatie van susceptibility genes
  • Validatie van beeldvormende technieken,

i.c. MRI-PDFF en transient elastography

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ANCHOR: Amsterdam NAFLD-NASH cohort

Prospective cohort study, double biopsy design Detect rapid progressors and better biomarkers – includes fecal samples

  • systems biology: hierarchy of driving mechanisms
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NAFLD susceptibility genes: the happy few

Blood Lipids NAFLD Teslovich, 95 loci, Nat Gen 2010 PNPLA3: TG hydrolase lipid droplets Klarin, 118 novel loci, Nat Gen 2018 TM6SF2: VLDL secretion MBOAT7: lysophospholipid remodeling (Land’s cycle) HSD17B13: modifier of PNPLA3, lipid droplets

Stols-Goncalves, Hovingh, Nieuwdorp, Holleboom Trends in Endocrinology and Metabolism, in press 2019

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New genes, from rare diseases: TMEM199, CCDC115

Lipophagy in non-alcoholic steatohepatitis: a translational journey from rare defects to treatment

  • Insights & targets

Models & cohort Lipophagy

Lipid droplet

Supported by Amsterdam UMC Fellowship

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  • Data collected:

✓ Questionnaire: sociodemographics, ethnicity, lifestyle, dietary habits, health, physical activity ✓ Physical examination: anthropometric measurements, clinical measurements, blood draw, medications, DNA, urine samples, vaginal and oral swabs for microbiome analyses ✓ Morning feces samples > 6000 subjects ✓ Detailed Food Frequency Questionnaires

Multiethnic HELIUS cohort (Healthy Life in an Urban Setting) in Amsterdam, The Netherlands

Daniela Stols-Goncalves, Onno Holleboom, Bert-Jan vd Born, Max Nieuwdorp

  • 22,165 participants (18-70 years) included between 2011

and 2016 ✓ 6 ethnic groups in similar proportions: Dutch, Surinamese (African and South-Asian descent), Turkish, Moroccan and Ghanaian ✓ Preferably 3 generations from one family (grandparents-children-grandchildren) included ✓ Otherwise healthy (at baseline visit 30-50% obese with signs of metabolic syndrome)

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  • 1. Setting up care paths for NAFLD

→ aging obese and diabetic population → more and more severe NASH → future drugs may also be prescribed by internists

  • Internist, also in particular vascular medicine: earlier identification
  • f patients with NASH, to prevent end stages: cirrhosis, HCC, asCVD.

Case finding: ALAT , ultrasound, Fib4 or Fibroscan

  • Dialoog met je hepatoloog?
  • 2. NAFLD research
  • Lots of open questions:
  • Prevalence and severity of NAFLD in NL
  • Genetic drivers
  • Key pathophysiological mechanisms – new targets for therapy
  • Role of the gut microbiome

Taken together: NAFLD, relevance for the internist

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Acknowledgements

Vascular Medicine AUMC

  • Prof. dr. Max Nieuwdorp

M.A. van den Boogert MD Lars Larsen MSc Julia Witjes MD → j.j.witjes@amsterdamumc.nl Anne-Marieke van Dijk MD Daniela Stols-Goncalves MD

  • Prof. dr. Harry Buller
  • Prof. dr. G. Kees Hovingh
  • Prof. dr. Bert Groen

Nienke Koopman MSc Veera Houttu MSc Aldo Grefhorst PhD Hepatology AUMC AMC: Prof. dr. Ulrich Beuers, dr. Takkenberg, dr. Willemse, drs. De Vries VUmc: dr. Sandjai Ramsoekh Hepatology, UMCU Utrecht

  • Dr. Saskia van Mil, dr. Joep de Bruijne

Pathology, AUMC: dr. Joanne Verheij Radboud University Nijmegen

  • Prof. dr. Dirk Lefeber

MDL, LUMC

  • Dr. Maarten Tushuizen
  • Amsterdam

NAFLD-NASH cohort study

Cardiovascular Institute Penn, Philadelphia Dan J. Rader, Nick Hand Clinical epidemiology & biostatistics AUMC Hadi Zaffermand

  • prof. Patrick Bosschuyt

Pediatrics AUMC

  • dr. Bart Koot

Laura Draijer MD

Amsterdam UMC Fellowship