nafld and nash - swedish.org/media/images/swedish/cme1/syllabuspdfs...1 nafld and nash kris v....
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![Page 1: NAFLD and NASH - swedish.org/media/Images/Swedish/CME1/SyllabusPDFs...1 NAFLD and NASH Kris V. Kowdley MD Director, Liver Care Network and Organ Care Research Swedish Medical Center,](https://reader031.vdocument.in/reader031/viewer/2022030508/5ab6e4cc7f8b9a7c5b8e2b0c/html5/thumbnails/1.jpg)
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NAFLD and NASH
Kris V. Kowdley MD Director, Liver Care Network and Organ
Care Research Swedish Medical Center, Seattle, WA
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Overview
• Epidemiology and Natural History of NAFLD.
• Current Challenges:
– 1. NAFLD is not a serious disease in young patients
– 2. Screening is not indicated even in high-risk populations
– 3. There is no FDA-approved treatment for NAFLD/Bariatric surgery cannot be recommended as Rx
• Discuss the management of NAFLD today.
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NAFLD is the Hepatic Manifestation of Obesity/IR
Metabolic Syndrome
• Insulin Resistance
• Dyslipidemia
• Hypertension
NAFLD
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NAFLD Prevalence
• Adults
– Overall: 30%
– Obese: 50-70%
– Severely Obese: 85%
– DM2: 65-75%
• Children
– Overall: 10%
– 15-19 years: 17%
– Obese: 50%
Loomba, et al. Nature Reviews. 2013; Schwimmer, et al. Pediatrics. 2006.
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The NAFLD Spectrum
80-100 Million
NAFL NASH/
Fibrosis
NASH
Cirrhosis HCC
NAFLD Activity Score
Steatosis (0-3)
5-33% 1
34-65% 2
≥66% 3
Inflammation (0-3)
<2 under 20x 1
2-4 under 20x 2
>4 under 20x 3
Ballooning (0-2)
Few 1
Many 2
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Annual Cumulative Incidence of HCC
2.6%/Year
4%/Year
Pro
po
rtio
n w
ith
HC
C
2.5 0.0 7.5 5.0 12.5 10.0 17.5 15.0 20.0 0.0
0.2
0.4
0.6
0.8
1.0 HCV NASH P = 0.099
Years Since Cirrhosis Diagnosis Ascha MS, et al. Hepatology. 2010.
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HCC in the Absence of Cirrhosis in US Veterans
Pe
rce
nt
NAFLD HCV HBV Alcohol Abuse
Idiopathic
66.2
33.8
88.9
11.0
92.3
7.7
91.1
8.9
65.4
34.6
0
20
40
60
80
100
Cirrhosis No cirrhosis El-Serag H, et al. CGH. 2015.
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Frequency of NASH as a Cause of Liver Transplantation in Adults
2001
2002
2003
2004
2005
2006
2007
2008
2009
Fre
qu
en
cy a
s In
dic
ati
on
(%
)
ALD HBV NASH PSC PBC AIH 0
5
10
15
20
Charlton, et al. Gastroenterology. 2011;141:1249.
*
*HCV frequency was ≈ 45%
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Burden of NAFLD Among Young Adults in the US
Mrad R. Alkhouri N, et al. Hepatology. 2016.
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Years Since Diagnosis
Surv
ival
(%
)
0 5 10 15 20 0
20
40
60
80
100
p<0.001
Expected Observed
A Hospital-Based Cohort Study n = 66 children with NAFLD, follow up for up to 20 years
2 patients developed NASH-cirrhosis that required LT at 20 and 25 years
Feldstein, et al. Gut. July 2009.
Natural History of NAFLD in Children
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LT for NASH in Children and Young Adults
Perc
en
t o
f P
ati
en
ts
Age at LT (Years)
0 10 20 30 40 0
10
20
30
40
Alkhouri, et al. Transpl Int. 2016.
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NASH Is the Most Rapidly Increasing Indication for OLT in Young Adults
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Current Screening for NAFLD: ALT and Ultrasonography
Degree of Steatosis
0
20
40
60
80
5-9% 10-19% 20-29% ≥ 30%
Sen
siti
vity
(%
) US Cannot Stage the Severity of Fibrosis in Patients
with NAFLD
Lee SS, et al. WJG. 2014.
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Staging the Severity of Steatosis and Fibrosis in NAFLD: VCTE + CAP
Actuator
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How Do I Manage My Patient with NAFLD
• 1. Rule out other etiologies of elevated ALT or fatty infiltration of the liver.
• 2. Assess for co-morbidities (DM2, HTN, Dyslipidemia, OSA).
• 3. Assess Severity (NASH, advanced fibrosis)
• 4. Treatment:
– Lifestyle
– Pharmacologic
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Assessment of the Severity of NAFLD
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Algorithm for Assessing the Severity of NAFLD
Patient with NAFLD
NFS + VCTE
• No advanced fibrosis • Consider repeating
every 2-3 years Liver Biopsy
• Advanced fibrosis • Screen for cirrhosis
complications • US every 6 months
NFS < -1.455 and
LSM < 7 Pa Discordant results
NFS > 0.676 and
LSM > 10 Pa
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Treatment: % Weight Loss Associated with Histological Improvement
Hannah WN, et al. Clin Liver Dis. 201.
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Changing the Attitude Toward Healthy Lifestyle in Texas
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Both Resistance Training and Aerobic Training Reduce Hepatic Fat Content
Baseline Baseline
Aerobic Training Resistance Training
*
He
pat
ic F
at C
on
ten
t, %
0
10
20
30
40
Aerobic Training
Per
cen
t C
han
ge f
rom
Bas
elin
e
in H
ep
atic
Fat
Co
nte
nt,
%
-45
-10
-20
-30
0
Resistance Training
-25
-15
-5
-4 -35
Moderate/ Vigorous Exercise: 30-45 min/day Bacchi E, et al. Hepatology. 2013.
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Weight Loss and NASH Improvement
Gastroenterology. 2015 Aug;149(2):367-78
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Weight Loss and Fibrosis in NASH
Gastroenterology. 2015 Aug;149(2):367-78
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Effects of Bariatric Surgery on Severe Liver Injury in Morbid Obese Patients with NASH
• 109 severely obese patients with biopsy-proven NAFLD had bariatric surgery
• Data were prospectively collected before and one year after surgery
• 64% gastric bypass, 29.4 gastric band
• BMI 49.3 37.4 kg/m2
Lassailly G, et al. University of Lille; Lassailly G, et al. Gastroenterology. 2015.
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Effects of Bariatric Surgery on Liver Histology
NASH grade evolution (Brunt score)
0%
20%
40%
60%
80%
100%
Before After
3
2
1
0
11%
25.6%
63.4%
1.2% 3.7% 9.8%
85.4%
Comparison of NASH grade distrbution p<0.00001
0%
20%
40%
60%
80%
100%
Before After
4
3
2
3.75% 7.5%
21.25%
40%
27.5%
7.5% 2.5%
13.75%
32.5%
43.75%
p<0.003
No NASH
NASH
NASH Disappearance
*Metavir scale. Significant improvement of Fibrosis lesions 1 year after bariatric surgery.
N= 82 patients with paired liver biopsies
Fibrosis Improvement
Fibrosis evolution
85% of NASH disappearance, 1 year after Bariatric surgery
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Endpoints in NASH Trials Trial Phase
Endpoint
Primary Secondary
Phase I/II • MRI-PDFF • ALT
• Decline in ALT • Decline in CK18 • Change in MRE
Phase II/III • Liver histology: NAS; resolution of NASH; improvement in fibrosis; delayed progression
• HVPG • Clinical outcomes • MELD
• MRI-PDFF/MRE • Decline in ALT • Decline in CK-18
Phase IV Long-term clinical outcomes
Abbreviations: ALT, alanine aminotransferase; CK18, cytokeratin-18; HVPG, hepatic venous pressure gradient; MELD, Model for End-Stage Liver Disease; MRE, magnetic resonance elastography; MRI-PDFF, magnetic resonance imaging-derived proton density-fat fraction; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis. Graphic courtesy of Rohit Loomba, MD.
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Phase III PIVENS Trial of Vitamin E or Pioglitazone in NASH—Primary Endpoint
43
19
34
0
10
20
30
40
50
Pat
ien
ts W
ho
Met
P
rim
ary
End
po
int
(%) P = .04
P = .001
NNT = 6.9
Abbreviations: NAS, nonalcoholic fatty liver disease score; NASH, nonalcoholic steatohepatitis, NNT, number needed to treat. Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685.
NNT = 4.2
n = 84
Primary endpoint = histologic improvement Defined as: ≥1-point improvement in hepatocellular ballooning score, no increase in fibrosis score, and either a decrease in NAS to ≤3 or a ≤2-point decrease in NAS plus ≥1-point decrease in either the lobular inflammation or steatosis score
Vitamin E 800 IU/day
Placebo Pioglitazone 30 mg/day
n = 83 n = 80
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Phase IIb FLINT Trial of Obeticholic Acid in NASH—
Primary Endpoint
21
45
0
10
20
30
40
50
Placebo OCA (25 mg)
Pati
en
ts W
ho
Met
Pri
mary
En
dp
oin
t (%
)
P = .0002
Abbreviations: NAS, nonalcoholic fatty liver disease score; NASH, nonalcoholic steatohepatitis; OCA, obeticholic acid. Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.
Primary endpoint = histologic response Defined as ≥2-point improvement in NAS and no worsening of fibrosis
n = 110 n = 109
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27/
144 8/144 11/145
29/
145 15/144
23/
145
Cenicriviroc Efficacy at 52 Weeks (CENTAUR)
• Dual inhibitor of C-C chemokine receptor 2 & 5 (CCR2/ CCR5)
• Phase IIb trial of 289 patients with NASH (NAS ≥ 4), liver fibrosis, DM/ MetS
Pts
(%
)
n/N =
19 16
100
80
60
40
20
0 Improvement in NAS ≥ 2 Points with No
Worsening of Fibrosis
6 8
Resolution of NASH
P = .49 P = .52
Improvement in Fibrosis
P = .02
10
20
Cenicriviroc 150 mg/day
Placebo
Sanyal AJ, et al. AASLD. 2016. Abstract LB-1.
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1/30 2/10 2/27
Selonsertib: Short-Term Efficacy at 24-Weeks
• Apoptosis signal-regulating kinase (ASK1) inhibitor.
• Phase II trial of patients with biopsy-confirmed NASH, NAS ≥ 5, F2-F3 liver fibrosis (N = 72)
Progression to Cirrhosis
Selonsertib 18 mg/day ± simtuzumab
Pts
(%
)
Simtuzumab
n/N = 13/30 8/27
30
43
100
80
60
40
20
0 Improvement in Fibrosis
Selonsertib 6 mg/day ± simtuzumab
2/10
20 7 3
20
Loomba R, et al. AASLD. 2016. Abstract LB-3.
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Gut Microbiome in NAFLD and NASH
Abbreviations: CCL, chemokine ligand; EtOH, ethanol; FFA, free fatty acids; Fiaf, fasting-induced adipocyte factor; HFD, high-fat diet; IL, interleukin; LPL, lipoprotein lipase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NLRP, nucleotide-binding domain, leucine-rich repeat protein; SCFA, short-chain fatty acids; TMA, trimethylamine; VLDL, very-low-density lipoproteins. With permission from Schnabl B, Brenner DA. Gastroenterology. 2014;146:1513-1524.
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Summary • NASH has along natural history • Many confounding factors in clinical outcomes
– Cardiovascular disease – Diabetes – Cancer – Weight loss
• Surrogate Endpoints Needed • Evolution from NASH resolution to fibrosis improvement • Blended endpoints to combine clinical benefit, surrogate markers