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

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%

NAFLD-NASH: hepatic component of MetSy

75% of DM2 has NAFLD

50% of hypertensives has NAFLD

→ mixed hyperlipidemia

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

NAFLD-NASH: major asCVD

‘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

NAFLD-NASH: major asCVD

‘Two sides of the same

dysmetabolic medal’

75% of DM2 has NAFLD

50% of hypertensives has

NAFLD

→ mixed hyperlipidemia

- Meta-analysis Wu et al, Sci Rep 2016:

164,494 participants, 21 cross-sectional

studies, and 13 cohort studies)

HR 1.9 - 2.3 n = 164,494

- 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

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?

Few validated

non-invasive tests

Few

outpatient clinics

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 guidelineTushuizen, Holleboom, …, Blokzijl, Koek

Capita Selecta NTVG, in revision

Case 1: mr. Y., ~50 years, Dutch descent

Algemene vasculaire spreekuur:

CVRM, secundaire preventie na OWI 2012

Worsening DM2, BMI 35

𝝲-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

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 descentRecently 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?

Involved in NAFLD-NASH

Sumida et al, NASH therapies, J Gastro-enterol 2018

Vascular Medicine

Diabetes nurses

GPs

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

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

Liver biopsy - activity

Liver biopsy - fibrosis

3. NAFLD: Pathophysiology & drug targets

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

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

Sizeable epidemic; enormous drug development

Yet: limited awareness! No guideline

Multidisciplinary approaches have started in NL; Belgium & UK ahead!

- Earlier case detection

Awareness amongst internists needs to improve

- endocrinology, vascular medicine, general internal medicine rotations; GPs

Sceptic standpoint that screening is not warranted since most patients have mild NAFLD and since

there is no treatment → holds no longer:

- Aging obese and diabetic population → more and more severe NASH, warrants awareness

- Future drugs will likely change clinical practice soon - fascinating yet major challenge

Dialogue hepatologist - diabetologist

4. Care for NASH patients in Amsterdam UMC

Since May 2018: outpatient NAFLD clinic

-- MetSy → NAFLD

-- fibroscan @ internal medicine

-- close collaboration with hepatology Beuers/Takkenberg

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:

- Retinopathy

- Nefropathy

- Neuropathy

- Hepatopathy – NAFLD-NASH

- screen infrequently;

- with a low threshhold

NAFLD-NASH in Amsterdam UMC: research

- ANCHOR study: Amsterdam NAFLD NASH cohort

- LITMUS: EU NAFLD registry

- CRISTINA: exercise intervention in NASH

- NILE: NAFLD in Helius multiethnic study Amsterdam ZO

Fundamental work

• Intrahepatic lipid storage – lipophagy defects

- completed Veni → Amsterdam UMC Fellowship 750 k€

• TKI-PPP grant 400 k€ for probiotics in NAFLD mouse models

• IEMs - iHeps – CRISPR-edited mouse models

ANCHOR: Amsterdam NAFLD-NASH cohort

Detect rapid progressors and better biomarkers

– includes fecal samples

- systems biology: hierarchy of driving mechanisms

- validate fibroscan against biopsy - gold standard

Witjes, Holleboom, Ramsoekh, Stols-Goncalves, Zwirs, Verheij, Beuers, Nieuwdorp

• 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

• 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)

Take home messageNAFLD-NASH: a progressive cardiometabolic disease

You have NAFLD patients

in your practice!

Some will have

progressive fibrosis!

Major asCVD

Call:

- MetSy / mixed dyslipidemia:

→ take the liver perspective

- Do ALAT, ultrasound, Fibroscan

- Have coffee with your hepatologist

Key points

• NAFLD-NASH: progressive cardiometabolic liver disease

• Strongly related to DM2 and MetSy

• You have NAFLD patients in your practice!

- obesity, mixed dyslipidemia, hypertension

• Some will have advanced fibrosis

• Please contact us for advice / referral:

a.g.holleboom@amsterdamumc.nl

NAFLD-NASH in Amsterdam UMC

• Current clinical practice falls short is improving

• Distinction between NAFLD and NASH

• Pathophysiology & drug targets

• NAFLD-NASH in AMC

- Patient care

- ANCHOR study & LITMUS registry