NAFLD and NASH - John A. Burns School of...

Tse-Ling Fong, MD, FACP, FAASLDAssociate Professor of Medicine

Keck School of Medicine

University of Southern California

Los Angeles, California

NAFLD and NASH

Disclosures

- Consultant

- Gilead

- Speakers’ Bureau

- Gilead

The Global Prevalence of NAFLD

Region N Prevalence (%) 95% CI (%) I2 (%)

Africa 2 13.48 (5.69 - 28.69) 84.37

Asia 14 27.37 (23.29 - 31.88) 99.17

Europe 11 23.71 (16.12 - 33.45) 98.78

Middle East 3 31.79 (13.48 - 58.23) 99.14

North America 13 24.13 (19.73-29.15) 99.19

South America 2 30.45 (22.74 - 39.44) 69.10

Overall 45 25.24 (22.1 - 28.65) 99.07

Younossi Z et al. Hepatology 2015

NAFLD: Most common cause of CLD and Cirrhosis

Setiawan VW, et al. Hepatology 2016

NAFLD Disease Progression

1. Ludwig J, et al. Mayo Clin Proc. 1980;55(7):434-438.2. Kleiner DE, et al. Hepatology. 2005;41(6):1313-1321.3. McPherson S, et al. J Hepatol. 2015;62:1148-1155.4. Singh S, et al. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54

70% to 75% 25% to 30%

Steatosis with

mild inflammation

Isolated

steatosis

NASH

FibrosisCirrhosis

Regression:

18%-22%

Stable:

40%-43%

Progression:

34-42%

Change in Fibrosis*[3,4]

*N = 108 pts with NAFL/NASH and median 6.6 yrs

follow-up (data from serial biopsies).

Histological Subtypes[1,2]

NAFLD

Mortality in Patients With NAFLD

Patients with NAFLD (N = 420) matched by age and sex to general population in Minnesota, followed for 7.6 ± 4.0 yrs

Adams LA, et al. Gastroenterology. 2005;129:113-121.

Top 3 Causes of

Death in NAFLD, %

Patients

(n = 53)

Malignancy 28

Ischemic heart disease 25

Liver disease 13

Survival at 10 Yrs

General population: 87%

Patients with NAFLD: 77%

Log-rank P < .005

0

20

40

60

80

100

0 4

Su

rviv

al

(%)

62 10

General populationPatients with NAFLD

P = .03

Yrs

8 12 14 16

Mortality Due to NASH Among Patients

With NAFLD

Patients with NAFLD (N = 129) matched by age and sex within same county in Sweden and followed for 13.7 yrs (SD: 1.3 yrs)

Ekstedt M, et al. Hepatology. 2006;44:865-873.

Su

rviv

al (%

)

0

20

40

60

80

100

0 5 2010 15Yrs

Su

rviv

al (%

)

0

20

40

60

80

100

0 5 2010 15Yrs

General population

Patients with NASH

P = .01

General population

Patients with nonalcoholic steatosis± unspecific inflammation

P = NS

NASHNonalcoholic Liver Steatosis ±

Nonspecific Inflammation

NAFLD & HCC

Dyson J et al; Hep 2014

Association Between NAFLD/NASH and

Diabetes Mellitus Is Bidirectional

Patients with NAFLD/NASH have:

Increased risk of developing diabetes[1,2]

Synergistic increase in risk of diabetes when combined with obesity or insulin resistance[3]

– Patients with obesity, NAFLD, or insulin resistance each have 2-4 x the risk of diabetes, but patients with all 3 have 14 x risk of diabetes

High prevalence of diabetes[4]

Patients with diabetes have:

Increased risk of NASH with family history of diabetes[5]

Increased risk of dying from cirrhosis[6,7]

Up to 3-fold increased risk of dying from chronic liver disease, mostly attributable to NAFLD[8]

Increased risk of chronic liver disease[9]

References in slidenotes.

Clinical Predictors of NASH in Patients

With NAFLD

Characteristic Outcome

Advanced age Greater duration of disease

SexPostmenopausal women experience accelerated

disease

Race↑ Prevalence, severity in Hispanic, Asian patients;

↓ Prevalence, severity in black patients

HTN, central obesity,

dyslipidemia (↑ TG, ↓ HDL),

insulin resistance/diabetes

Risk increases with metabolic syndrome,* 66%

prevalence of bridging fibrosis if older than 50 yrs

of age and obese or diabetic[5,6]

AST/ALT ratio > 1,

low plateletsIndicators of NASH cirrhosis

Persistently elevated ALTCan be associated with greater risk of disease

progression

*Based on ATP III criteria.

Normal ALT Does Not Rule Out

Progressive Disease in NAFLD or NASH

Persistently elevated ALT can be associated with disease progression[1]

Patients with normal ALT levels can also develop progressive disease[2-4]

– Up to 80% of NAFLD patients can have normal ALT[5]

No designated ALT cutoff for prediction of NASH or advanced fibrosis in NAFLD pts[6]

1. Ekstedt M, et al. Hepatology. 2006;44:865-873. 2. Maximos M, et al.

Hepatology. 2015;61:153-160. 3. Mofrad P, et al. Hepatology.

2003;37:1286-1292. 4. Amarapurkar DN, Patel ND. Trop Gastroenterol.

2004;25:130-134. 5. Dyson JK, et al. Frontline Gastroenterol.

2014;5:211-218. 6. Verma S, et al. Liver Int. 2013;33:1398-1405.

Noninvasive Diagnosis of Liver Fibrosis in

NAFLD

Simple

AST/platelet ratio

index

FIB-4 index

NAFLD fibrosis

score

BARD score

Complex

NASH FibroSure

ELF

HepaScore

Elastography

VCTE FibroScan

MR elastography

ARFI

Clinical or Laboratory Tests Imaging

NAFLD Fibrosis Score

Parameter

Age, yrs

AST

ALT

Platelet count, cells x 109

BMI

Albumin, g/L

Impaired fasting

glucose/diabetes?

NAFLD Cutoff Value[1] Stage

< -1.455 F0-F2

-1.455 to 0.676 Indeterminate

> 0.676 F3-F4

FIB-4 Cutoff Value[2] Stage

< 1.45 F0-F2

1.45 to 3.25 Indeterminate

> 3.25 F3-F4

FIB-4 score:NAFLD

Fibrosis Score:

1. Angulo P, et al. Hepatology. 2007;45:846-854.

2. Sterling RK, et al. Hepatology. 2006;43:1317-1325.

Tools for Diagnosis of NAFLD


Method Sensitivity Specificity Comments

Liver enzymes

GGT[1] 63% 65% Not reliable for diagnosis

Ultrasound[2]

Any degree[3]

Cutoff ≥ 20%[3]

CT without contrast[4]

Cutoff > 30%

MRI[5]

Cutoff PDFF 6.4%, gr ≥ 1

Cutoff PDFF 17.4%, gr ≥ 2

MRS[6]

Cutoff ≥ 5%

Cutoff > 33%

85%

61%

100%

79%

86%

64%

90-96%

92-100%

94%

100%

90%

97%

83%

96%

87-100%

92-97%

Inexpensive and accessible,

but cannot distinguish

fibrosis/steatosis

Better in morbid obesity, but

affected by iron, fibrosis, and

less accurate with less

steatosis

Detects mild steatosis,

quantifies hepatic fat most

accurately

Liver biopsy Gold standard, but invasive

and subject to sampling error

Diagnostic Performance of Supersonic

Shear Imaging, FibroScan, and ARFI

Fibrosis Stage AUROC (95% CI) Best Accuracy, % (n/N)

Supersonic shear imaging

≥ F2

≥ F3

F4

0.86 (0.79-0.90)

0.89 (0.83-0.92)

0.88 (0.82-0.92)

80 (185/232)

85 (196/232)

87 (202/232)

FibroScan (M probe only)

≥ F2

≥ F3

F4

0.82 (0.76-0.87)

0.86 (0.80-0.90)

0.87 (0.79-0.92)

77 (172/223)

79 (175/223)

89 (198/223)

ARFI

≥ F2

≥ F3

F4

0.77 (0.70-0.83)

0.84 (0.78-0.89)

0.84 (0.78-0.89)

74 (175/236)

79 (186/236)

84 (199/236)

Cassinotto C, et al. Hepatology. 2016;63:1817-1827.

Can Noninvasive Clinical or Lab Tests

Distinguish NASH Stages 0-2 vs 3-4?

Strength of noninvasive fibrosis predictive tests is in their ability to exclude advanced disease (F3-F4)

– Least accurate in identifying middle ranges of fibrosis

McPherson S, et al. Gut. 2010;59:1265-1269.

McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print].

0 20 10060 80Specificity (%)40

FIB4 scoreAST/ALTBARDAPRINAFLD

Sen

sit

ivit

y (

%)

0

20

40

60

80

100

9593958492

Negative Predictive Value for F3-F4 (%)[1]

Magnetic Resonance Elastography

In NAFLD, higher diagnostic accuracy for fibrosis vs transient elastography and CPRs,[2,3] can accurately predict advanced fibrosis[4]

Inflammation can increase stiffness values in the absence of fibrosis[1]

Stiffness[1]

High Low

Reprinted, with permission, from Radiology 2011;259:749-756. ©RSNA.


Inflammation,

But No Fibrosis

FibrosisSimple Steatosis

The Role of Liver Biopsy

Make diagnosis of NASH (surrogates insufficient)[1]

– Initiate drug therapy

– Assess prognosis: liver, cardiovascular, etc

Stage fibrosis (if imaging or tests are indeterminate)[1]

Rule out concomitant liver disease[1]

– Autoimmune, Wilson disease, DILI, iron overload (ferritin can be high in NAFLD in absence of iron overload[2])

Isolated Steatosis Steatohepatitis/NASH

1. Rinella ME, et al. Gastroenterol Hepatol (NY). 2014 ;10:219-227.

2. Camaschella C, Poggiali E. Haematologica. 2009;94:307-309.

Fibrosis Staging in NASH

F1: Perisinusoidal F2: Perisinusoidal + Portal

F3: Bridging Fibrosis F4: Cirrhosis

Prognostic Relevance of Liver Histology in Nonalcoholic Fatty Liver Disease: The PRELHIN study

International study of

NAFLD (N=619) diagnosed

between 1975-2005

All liver biopsies centrally

ready

Median follow-up 12.6 yrs

193 who died or had OLT• 74 (38.3%) of CV disease

• 36 (18.7%) of non-liver CA

• 18 (9.3%) of liver complication

Angulo P et al Gastroenterology 2015

Fibrosis

Stage

Hazard Ratio (95% CI) P value

0

1

2

3

4

1 (ref)

2.4 (0.63, 8.91)

7.5 (2.26, 24.94)

13.8 (4.35, 43.65)

47.5 (11.94, 188.61)

0.2

0.01

< 0.001

< 0.001

Multivariate Analysis

Because “Histologic NASH” and “stage of fibrosis” are predictors of

mortality, they have become important study endpoints

Management Strategies

Identification of the risk of NASH and disease progression is guided by:

– Clinical risk factors (eg, metabolic, family history)

– Noninvasive markers

– Fairly accurate to diagnose advanced fibrosis

– Know the confounders

– Lesser cutoffs on imaging in combination with other factors can predict NASH with modest accuracy

– Can reliably exclude advanced fibrosis but not NASH

Risk Stratification in Pts With Suspected

NAFLD

Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016;13:196-205.

Reprinted by permission from Macmillan Publishers Ltd.

Low-risk profile

BMI < 29.9

Age < 40 yrs

No T2DM or

metabolic syndrome

features

Noninvasive fibrosis

estimation:

• FIB-4 < 1.30

• APRI < 0.5

• NFS < -1.455

FibroScan < 5 kPa

Intermediate-risk

profile

BMI > 29.9

Age > 40 yrs

Multiple features of

the metabolic

syndrome


estimation:

• FIB-4 1.30-2.67

• APRI 0.5-1.5

• NFS -1.455-0.675

FibroScan 6-11 kPa

High-risk profile

AST level > AST level

Platelets < 150,000


estimation:

• FIB-4 > 2.67

• APRI > 1.5

• NFS > 0.675

FibroScan > 11 kPa

Hepatic steatosis on imaging

± elevated serum ALT levels

Evaluate alcohol

consumption

Confirm NAFLD Exclude alternate

causes of ↑ALT levels

Follow and reassess as

risk factors evolve Consider liver biopsy

Consider liver biopsy or

confirmatory testing for

cirrhosis (eg, MRE)

Percentage of Weight Loss Associated

With Histological Improvement in NAFLD

Analysis of data from 4 randomized studies

*Depending on degree of weight loss.

Hannah WN, et al. Clin Liver Dis. 2016;20:339-350.

Weight loss ≥ 5%

Weight loss ≥ 7%

Weight loss ≥ 10%

Weight loss ≥ 3%

Fibrosis

regression(45% of pts)

NASH resolution(64% to 90% of pts)*

Ballooning/inflammation(41% to 100% of pts)*

Steatosis(35% to 100% of pts)*

Double-blind, placebo-controlled, randomized, phase III trial in adults with biopsy-proven NASH and no diabetes or cirrhosis (N = 247)

PIVENS: Histologic Resolution of NASH at

Wk 96 With Vitamin E vs Pioglitazone

47

33/70

Vitamin E800 IU/day

Placebo0

20

40

60

80

100

36

21

P = .05

n/N = 15/7229/80

Pioglitazone30 mg/day

P = .001

Pts

Wit

h R

eso

lved

NA

SH

(%

)

Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685.

Randomized, placebo-controlled, double-blind phase IV trial of pts with NASH and prediabetes or type 2 diabetes mellitus (N = 101)[1]

– Secondary outcome analysis of histologic scores included pts with paired biopsies from before/after tx (n = 82)

Pioglitazone in Diabetes: Improvement or

Resolution of NASH at 18 Mos

1. ClinicalTrials.gov. NCT00994682.

2. Cusi K, et al. Ann Intern Med. 2016;165:305-315.

Placebo (n = 42)

100

80

60

40

20

0

Pts

Wit

h Im

pro

vem

en

t (%

)

P < .001 P = .001

≥ 2-Point Reduction

in NAS

(No Worsening

of Fibrosis)

Resolution

of NASH

Pioglitazone (n = 40)

19

65

21

58

Pharmacologic Treatment Options Studied

in NASH

Agent Good Evidence

for Use[1]

Limited or

Insufficient Evidence

for Use[1]

AASLD

NAFLD/NASH

Recommendation[2]

Vitamin ENASH without

diabetes

NASH with diabetes or

cirrhosis

NASH without

diabetes

PioglitazoneNASH with or

without diabetesNASH with cirrhosis

Can be used for

steatohepatitis

MetforminNo significant effect

on liver histology[2] Not recommended

Pentoxifylline

Needs further study to

determine ideal

subpopulation

1. Rinella ME, et al. Gastroenterol Hepatol. 2014;10: 219-227.

2. Chalasani N, et al. Hepatology. 2012;55:2005-2023.

Bariatric Surgery Improves Fibrosis in Pts

With NASH

Prospective study of bariatric surgery in pts who are morbidly obese with biopsy-validated NASH, ≥ 1 comorbidity factor for > 5 yrs, no chronic liver disease (N = 109)

Lassailly G, et al. Gastroenterology. 2015;149:379-388.

Distribution of Fibrosis METAVIR Scores

Baseline After 1 Yr

Pts

(%

)

Wilcoxon signed-

rank paired t test

P < .003

F4

F3

F2

F1

F0

100

80

60

40

20

0

3.757.5

2.57.5

21.25

40

27.5

13.75

32.5

43.75

Fibrosis METAVIR Score

FXR Central to a Multitude of Key

Pathways in Animal Models

↑ Cholesterol

↓ Bile acids

CYP7a1

↓ Fibrosis

↓ Hepatic

triglycerides

↑ Glucose toleranceMultiple mechanisms

via ↓ SREPB-1C

RX

R

via ↑ β-oxidation

↓ stellate cell

activation

via ↑ iNOS↓ Portal

pressure


FXR agonist

(eg, obeticholic acid)

Emerging Treatments in NASH: Phase III

1. Ratziu V, et al. Gastroenterology. 2016;150:1147-1159.


3. Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.


5. Ratziu V, et al. EASL 2016. Abstract THU-488.

Drug Mechanism of

Action

Study

Population

Trial Primary

Endpoint(s)

ElafibranorPPAR α/δ

agonist[1]

NASH with

fibrosisRESOLVE-IT[2]

Resolution of NASH

w/o fibrosis

worsening

Obeticholic

acid

FXR agonist

(bile acid)[3]

NASH with

fibrosisREGENERATE[4,5]

Improvement in

fibrosis w/o NASH

worsening;

improvement in

NASH w/o fibrosis

worsening

~ 90 x increased potency

6α ethyl substitution

CDCA

chenodeoxycholic acid

OCA (6-ECDCA)

obeticholic acid

FXR EC50 = 99 nM= 8.7 µM FXR EC50

Obeticholic Acid: FXR Agonist and Bile

Acid Analogue

In vitro/in vivo studies do not necessarily correlate with clinical response

Pellicciari R, et al. J Med Chem. 2002;45:3569-3572.

OH

O

OHHO

Me

Me

OH

O

OHHO

Me

Me

Dual PPARa/d Agonist

Elafibranor

PPARa

• Fatty acid oxidation

• TG lowering

• HDL raising

• Inflammation

Liver

PPARd

• Lipoprotein metabolism

• Glucose homeostasis

• Energy metabolism

• Inflammation

Slide courtesy of Bart Staels, MD.


Key NASH Therapies: Improvement in

Steatosis

Results from separate studies, not head to head

– Time points and populations may differ between studies

In bariatric surgery study, median steatosis improved from 60% at baseline to 10% at 1 yr[6]

Active drug

Pts

(%

)

Placebo

n/N = 23/145 27/144

54

31

61

38

19

69

31

83

45

35

1816

Vitamin E

800 IU/day[1]

Pioglitazone

30 mg/day[1]

Liraglutide

1.8 mg/day[2]

Obeticholic

Acid 25

mg/day[3]

Elafibranor

120 mg/day[4]

100

80

60

40

20

0Cenicriviroc

150 mg/day[5]

P = .005P < .001

P = .009

P = .001

P = .10

P = .52

11/31 7/3962/102 37/9819/23 10/2248/70 22/7243/80 22/72

Key NASH Therapies: Resolution of NASH


Bariatric

Surgery[6]

Pts

(%

)

11/

145

8/

144

36

21 22

13

85

6

47

21

39

929

58

Vitamin E

800

IU/day[1]

Pioglitazone

30 mg/day[1]

Liraglutide

1.8 mg/day[2]

Obeticholic

Acid 25

mg/day[3]

Elafibranor

120 mg/day[4]

100

80

60

40

20

0Cenicriviroc

150 mg/day[5]

P = .05

P = .001P = .019

P = .08 P = .01 P = .49

Active therapyPlacebo

n/N =29/

80

15/

72

33/

70

15/

72

9/

23

2/

22 22/

102

13/

98

9/

31

2/

39 70/

82



29/

14515/

144

41

31 35

19

34

10

44

3126

1420


P = .24 P = .12

P = .46

P = .004

No data

P = .02

Key NASH Therapies: Improvement in

Fibrosis



33/

80

22/

72

31/

70

22/

72

6/

23

3/

22

36/

102

19/

98

27/

80

Active therapyPlacebo

Bariatric

Surgery[6]

Vitamin E

800 IU/d[1]

Pioglitazone

30 mg/d[1]

Liraglutide

1.8 mg/d[2]

Obeticholic

Acid 25

mg/d[3]

Elafibranor

120 mg/d[4]

100

80

60

40

20

0Cenicriviroc

150 mg/d[5]

Pts

(%

)

n/N =

Summary

Lifestyle changes are the foundation of any treatment plan

– Weight loss ≥ 3% to 10% associated with histologic improvement in NAFLD

AASLD guidance cites evidence for vitamin E (NASH without diabetes), pioglitazone (NASH with or without diabetes), bariatric surgery

Preliminary evidence for improvement in fibrosis with some investigational therapies

NAFLD and NASH - John A. Burns School of...

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