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1
NAFLD and NASH
Kris V. Kowdley MD Director, Liver Care Network and Organ
Care Research Swedish Medical Center, Seattle, WA
2
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.
3
NAFLD is the Hepatic Manifestation of Obesity/IR
Metabolic Syndrome
• Insulin Resistance
• Dyslipidemia
• Hypertension
NAFLD
4
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.
5
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
6
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.
7
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.
8
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%
9
Burden of NAFLD Among Young Adults in the US
Mrad R. Alkhouri N, et al. Hepatology. 2016.
10
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
11
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.
12
NASH Is the Most Rapidly Increasing Indication for OLT in Young Adults
13
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.
14
Staging the Severity of Steatosis and Fibrosis in NAFLD: VCTE + CAP
Actuator
15
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
16
Assessment of the Severity of NAFLD
17
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
18
Treatment: % Weight Loss Associated with Histological Improvement
Hannah WN, et al. Clin Liver Dis. 201.
19
Changing the Attitude Toward Healthy Lifestyle in Texas
20
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.
21
Weight Loss and NASH Improvement
Gastroenterology. 2015 Aug;149(2):367-78
22
Weight Loss and Fibrosis in NASH
Gastroenterology. 2015 Aug;149(2):367-78
23
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.
24
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
25
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.
26
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
27
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
28
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.
29
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.
30
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.
31
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
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