een vet probleem A.G. (Onno) Holleboom, endocrinoloog; per 31-12 vasc - - PowerPoint PPT Presentation
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)
A.G. (Onno) Holleboom, endocrinoloog; per 31-12 vasc gnk, Vasculaire Geneeskunde | 14-05-’19
Disclosures
Hardy, Anstee, Ann Rev Pathol 2016
Younossi, Hepatology 2016; Paris NASH meeting 2018
Zhou et al, Hepatology. 2019 May 9
Estes, Hepatology 2018
Younossi, Z. et al., Nat. Rev. Gastroenterol. Hepatol. 2017 Koehler et al, Hepatology 2016
Worldwide estimated prevalence of NAFLD
Rotterdam study - 3,041 participants general population > 45 years: transient elastography: significant liver fibrosis in 5.6%
75% of DM2 has NAFLD 50% of hypertensives has NAFLD → mixed hyperlipidemia
Hardy, Anstee, Ann Rev Pathol 2016, after Donnelly, JCI 2015 Continuous NEFA flux, independent of feeding – metabolic inflexibility LXR, FAS
Isokuortti, Diabetologia 2017
‘Two sides of the same dysmetabolic medal’
75% of DM2 has NAFLD 50% of hypertensives has NAFLD → mixed hyperlipidemia
Targer, NEJM 2010 Friedman, Nature Medicine 2018, Stols-Goncalves, Holleboom, Nieuwdorp, Hovingh, Trends in Endocrinology in press 2019
‘Two sides of the same dysmetabolic medal’
75% of DM2 has NAFLD 50% of hypertensives has NAFLD → mixed hyperlipidemia
164,494 participants, 21 cross-sectional studies, and 13 cohort studies) HR 1.9 - 2.3 n = 164,494
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
Framingham Heart Study: congruent
Targer, NEJM 2010 Friedman, Nature Medicine 2018, Stols-Goncalves, Holleboom, Nieuwdorp, Hovingh, Trends in Endocrinology in press 2019
In my view: atherogenic, mixed dyslipidemia – hypersecretion of VLDL Liver has 4 protective mechanisms against lipid overload in NAFLD
Support from Mendelian randomization studies (Romeo Gothenburg; CCHS group Copenhagen):
Ergo:
Few validated non-invasive tests
Few
in NL
No approved treatment; many trails and compounds underway Need for detection of early cases to prevent fibrosis/cirrhosis/asCVD
Scepsis
Case finding No Dutch guideline
Tushuizen, Holleboom, …, Blokzijl, Koek Capita Selecta NTVG, in revision
Algemene vasculaire spreekuur: CVRM, secundaire preventie na OWI 2012 Worsening DM2, BMI 35 𝝳-GT 67 U/l (0-40) ALAT 85 U/l (0 – 34) Fibroscan elastography: LSM: 17 kPa (<7) CAP: 354 dB/m Other causes such as alcohol, viral hepatitis and hemochromatosis: excluded No biopsy due to anticoagulant use C/ NASH-related cirrhosis, CPA B/ initiated liraglutide for his worsening DM
Recently hypertensie-poli: malaise despite well controlled hypertension & DM2 Alkaline phosphatase 128 (40 - 120 U/L), gamma-GT 504 U/l (0-40), ASAT 83 U/l (0- 40), ALAT 79 U/l (0 – 34) Ultrasound of liver: Coarse parenchyma, uneven contours, prominent caudate lobe, maximal diameter 12 cm (15). Reduced hepatopetal flow in portal vein: 6-8 cm/s (20-40) Fibroscan: 75 kPa (<7) Other causes such as viral hepatitis and hemochromatosis: excluded Biopsy: NASH-related cirrhoses →1992 evaluation including biopsy OLVG-O – prolonged course → Need for earlier detection and management → We see the target population for early management, not the hepatologists → Pure endocrinologists don’t care about MetSy?
Sumida et al, NASH therapies, J Gastro-enterol 2018
Vascular Medicine Diabetes nurses GPs
2016 Fibrosis-4 score, Fib-4: ( Age x AST ) / ( Plts x ( sqr ( ALT ) )
Shah et al, Clin Gastro Hepatol 2009
Validated values for fibrosis staging: F0-F1 F2 F3 F4 ≤7.0 ≥7.5 ≤10 ≥14.0 kPa
Eddowes, Gastroenterology 2019(1)
Fibroscan, 2nd measure: steatosis, with controlled attenuation parameter (CAP , dB/m)
Eddowes et al, Gastroenterology 2019(1): first prospective validation of Fibroscan - transient elastography
Arab & Trauner, Annu Rev Pathol 2018 Dongiovanni & Anstee, Curr Pharm Des 2013
Insulin resistance GLP1 agonists Phase 2 LEAN trial with liraglutide:
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
Positive trial
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
murine model FMT trial, manuscript in preparation (Smits, Witjes, Nieuwdorp) For review: Koopman, Molinaro, Nieuwdorp, Holleboom, Aliment Pharm Ther, accepted 2019
Sizeable epidemic; enormous drug development Yet: limited awareness! No guideline Multidisciplinary approaches have started in NL; Belgium & UK ahead!
Awareness amongst internists needs to improve
Sceptic standpoint that screening is not warranted since most patients have mild NAFLD and since there is no treatment → holds no longer:
Since May 2018: outpatient NAFLD clinic
Since March 2019: Multidisciplinary outpatient clinic at VUmc Together with Sandjai Ramsoekh, dietician, lifestyle coach In touch with NHV Amsterdam; platforms AUMC @ Internal medicine, endocrinology, vascular medicine: All DM2 patients:
Fundamental work
Detect rapid progressors and better biomarkers – includes fecal samples
Witjes, Holleboom, Ramsoekh, Stols-Goncalves, Zwirs, Verheij, Beuers, Nieuwdorp
✓ 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
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)
You have NAFLD patients in your practice! Some will have progressive fibrosis! Major asCVD Call:
→ take the liver perspective
, ultrasound, Fibroscan
a.g.holleboom@amsterdamumc.nl