1

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.

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

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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