Non-alcoholic Fatty Liver disease (NAFLD):

Pathogenesis – Natural History

Advances in Management and Treatment

HASLD 2019

Robert G Gish MD

Medical Director Hepatitis B Foundation

Robert Gish Consultants LLC

San Diego, California

A Disturbing Evolutionary Development

© 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG

3

Rinella. Hep 2016

NAFLD Seen Globally

The NAFLD Continuum

Steatohepatitis “NASH”

Cirrhosis Normal Liver Steatosis “NAFL”

NAFLD

Slide credit: clinicaloptions.com

Fatty liver with inflammation and

hepatocyte ballooning

Increasing fibrosis leading to cirrhosis,

hepatocellular carcinoma

Worldwide prevalence: ~ 25% 1.50% to 6.45%

Fatty liver without inflammation or

hepatocyte ballooning

Chalasani. Hepatology. 2018;67:328.

Abdominal obesity

Glucose intolerance/

insulin resistance

Hypertension

Atherogenic dyslipidemia

Proinflammatory/

prothrombotic state

Metabolic Syndrome and Its Hepatic Manifestation

National Cholesterol Educational Program (NCEP), Adult Treatment Panel (ATP) III; 2001.

Diabetes NAFLD

CVD NASH

2nd

hit

Insulin

Resistance

3rd

hit

Normal

Liver Steatosis

NASH Fibrosis

Pathogenesis of NASH The Multi-hit Hypothesis

The Metabolic

Syndrome

1st

hit

•Cytokines

•Adipokines

•Oxidative stress

•Apoptotic pathways

•Others

Risk Factors for NAFLD

Major Co-morbidities

Type 2 Diabetes

Dyslipidemia

Obesity

Metabolic Syndrome

HTN

Emerging Associations

Hypothyroidism

Sleep Apnea

Hypopituitarism

Polycystic Ovary Syndrome

Lonardo A, et al. J Hepatol 2006; 44: 1196-1207

McCullough A et al. J Clin Gastroenterol 2002;34:255-262

Fructose

• Dietary Carbohydrates can be converted to fat in

the liver

• Fructose (alone or as part of sucrose) drives

lipogenesis and promotes NAFLD

• Epidemiologic studies, clinical trials, and animal

studies show that excess carbohydrate

consumption contributes to NAFLD

• High fructose consumption depletes hepatic ATP

and impairs recovery from ATP depletion

Abdelmalek M, Hepatology 2012

NAFLD and Ethnicity

• Hepatic TG content by MRS* in 2,287 subjects

• 32.1% White, 48.3% Black, 17.5% Hispanic

• One-third had hepatic steatosis

• 45% Hispanics, 33% Whites, 24% Blacks

• Most (79%) had normal serum ALT

• Steatosis related to IR, obesity in Hispanics

• Not related to these risk factors in Blacks

• Steatosis > Men:Women except in Blacks

Browning et al. Hepatology. 2004 ;40:1387-95

*proton magnetic resonance spectroscopy

NASH Prevalence Among Ethnic Groups

Pre

vale

nce (

%)

12.2

19.4

9.8

13.5

6.7

N=14/72 N=20/205 N=5/37 N=40/328 N=1/14

Williams, Gastroenterology 2011

The intestinal microbiome modulates

insulin resistance and metabolism

Gravitz, Nature 2012, 485, S12-13

Cassano, M. and Dufour, J.-F.

(2019), Inflammation and

Microbiota Fingerprint:

Delphi’s Oracle for NASH

–Related Hepatocellular Carcinoma

Hepatology, 69: 12-15. doi: 10.1002/hep.30267

Before diet therapy, obese people had fewer

Bacteroidetes (P<0.001) and more Firmicutes (P=0.002)

than did lean controls

Nature 444, 1022-1023(21 December 2006)

Genetic Modifiers of NAFLD Risk & Progression

NASH Normal Cirrhosis HCC

Non-progressive By itself

15%

Ludwig 1980 , Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Matteoni 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos

2001, Ong 2001,, Bugianesi 2002, Ratziu 2002, Harrisson 2003, Marchesini 2003, Younossi 2004, Fassio 2004Sanyal 2004, Ong 2005,

Adams 2005, Ong 2006, Rafiq 2008

Simple

Steatosis

Consequences of NAFLD

?

IS NAFLD Progressive?

Outcomes in NAFL-D

Williams Annals of Internal Medicine 2011

Liver-Related and Overall Mortality in

Patients with NAFLD

Lomonaco & Cusi, 2012

Table 2. Long-term liver-related and overall mortality in middle-aged patients with NAFLD.

¶ When compared to the general population.

* Median.

NR: not reported.

Author n

Follow-up

(mean, yrs)

Liver-related

mortality

Overall

mortality

Increased

Mortality¶

Simple

Steatosis

Matteoni et al (1999) 49 9 2.0% 33.0% No

Ekstedt et al (2006) 58 14 0.0% 12.1% No

Rafiq et al (2009) 74 19* 2.7% 56.8% No

Soderberg et al (2010) 67 21 3.0% 34.3% No

Dam-Larsen et al (2009) 170 21 0.6% 28.2% No

Total/mean 418 17 1.7% 32.9%

NASH Matteoni et al (1999) 29 8 10.0% 30.0% Yes

Ekstedt et al (2006) 71 14 2.8% 26.8% Yes

Rafiq et al (2009) 57 19* 17.5% 63.2% Yes

Soderberg et al (2010) 51 21 5.9% 47.1% Yes

Evans et al (2002) 26 9 - 15.0% Yes

Adams et al (2005) 49 8 8.1% 35.0% Yes

Younossi et al (2011) 131 10* 15.7% 21.3% NR

Total/mean 349 11 8.6% 34.1%

NAFLD- Hui et al (2003) 23 7 21.0% 26.0% NR

related Sanyal et al (2006) 152 10 14.5% 19.1% NR

cirrhosis Yatsuji et al (2009) 68 5 7.3% 27.9% NR

Bhala et al (2011) 247 7 5.7% 13.4% Yes

Total/mean 490 7 12.1% 24.3%

Clinical Features of NAFL/NASH

Work up of patients with NAFLD

Imaging Techniques for Evaluating

Hepatic Steatosis

Ultrasound, liver, full abdomen

Elastography

VCTE (Fibroscan), 2D, Point, MRE

Computed tomography

Magnetic resonance imaging

Percent fat calculations

Estimated protein-density fat-fraction

Magnetic resonance elastography

Controlled attenuation parameter

For fat using FibroScan

How to establish diagnosis of NAFLD

and identify patients with NASH?

Patients with NAFLD or NASH are generally asymptomatic

Clinical presentations cannot distinguish NASH

Current radiologic modalities are unable to distinguish NASH or accurately detect fibrosis

Non-invasive biomarkers are not established (getting closer)

Therefore, in 2017, liver biopsy remains “the imperfect gold standard” to diagnosis and stage NASH

Clinical Factors that are different between

Isolated Fatty Liver and NASH

Clinical Variable Not NASH (n=89) NASH (n=40) P Value

BMI 31.7 (5.3) 34.4 (5.4) 0.01

Fasting Insulin 14 (8.4) 23.2 (13) <0.0005

ALT (U/L) 36.2 (15.7) 50.9 (19.6) <0.0005

AST (U/L) 25.6 (7.4) 36.3 (13.1) <0.0005

HDL (mg/dL) 49.2 (15.7) 44.3 (9) 0.03

Adiponectin (ng/mL) 11028 (13078) 7815 (4811) 0.02

hsCRP (ng/mL) 5355 (5537) 7351 (6397) 0.04

CK-18 (U/L) 210.3 (118) 307.1 (233.1) 0.02

Williams CD, Gastroenterology 2011

NAFLD: sonographic evidence

• Bright liver

• Echotexture increased

compared to kidney

• Vascular blurring

CT scan: fatty liver

NO-CONTRAST CONTRAST-ENHANCED

Fat in the liver may be focal

Histopathology of NASH:

Necessary Components for a Diagnosis

Chalasani N, et al. Hepatology. 2012;55:2005-2023. Takahashi Y, et al. World J Gastroenterol. 2014;20:15539-15548. Kleiner DE, et al. Clin Liver Dis. 2016;20:293-312.

Steatosis (≥5%)

Macro>Micro

Accentuated in zone 3

Periportal areas usually spared in early disease

Lobular Inflammation

Any degree (mixed, mild)

Scattered polymorphonuclear leukocytes as well as

mononuclear cells

Hepatocellular Ballooning

Most apparent near steatotic liver cells Typically zone 3

+ +

Histopathology of NASH:

Helpful Features, But Not Required for Diagnosis

Mallory-Denk Bodies

Large cytoplasmic inclusions seen in ballooned hepatocytes

Protein aggregates comprising misfolded keratins

Apoptotic Bodies

(dark arrows)

Also known as acidophil bodies

Correlate with disease activity

Commonly present with ballooned hepatocytes and lobular infiltrates

(white arrows)

Perisinusoidal Fibrosis

Typically zone 3

Delicate collagen strands between ballooned

hepatocytes

Yeh MM, et al. Hum Pathol. 2016;52:28-37. Kleiner DE, et al. Clin Liver Dis. 2016;20:293-312.

NAFLD studies in Vietnam

• A descriptive study: 250 NAFLD patients detected on ultrasound

• Aim: Evaluate cardiovascular risk factors

• Results: Overweight-obesity: 54.8%; Hypertension: 38%; Pre-diabetes:

36.4%, Diabetes: 22%; Dyslipidemia: increased Triglyceride 70.8%

• Framingham score: Risk of coronary heart disease increase with the severity

of NAFLD (Grade I, II, III: 38.8%, 42.9%, 62.5%)

Le Thi Dung et al 2015. Military hospital 121.

NAFLD study in Vietnam

• Population: 2-15 yo, overweight/obese children

• Aim: To evaluate dyslipidemia and NAFLD

• Results: N = 40

- All patients: dyslipidemia

- NAFLD: 40% - mainly grade I (81.3%)

- Correlation between cholesterol, triglyceride level and

NAFLD presence

Trinh Thi Ngoc Van et al (2014). Hue hospital

NAFLD studies in Vietnam

• A descriptive study on NAFLD patients 2014 – 2016, 108 Military hospital

• Aim: To describe clinical manifestation, histopathology results

• Results: N=43

Vo Thi Thu Trang et al (2018). 108 Military hospital

NAFLD studies in Vietnam

n %

Overweight 16 37.2

Obese 26 60.4

Abdominal obesity 40 93.0

BMI (Mean) 25.42 ± 1.52

11.6%

88.4%

NASH: 88.4%

Vo Thi Thu Trang et al (2018). 108 Military hospital

NAFLD studies in Vietnam

• Macrovesicular steatosis 72.1%, lobular inflammation 97.7%

(mild and moderate); portal inflammation 72,1% (mild and moderate).

• Fibrosis 93% (stage 1a, 1b and 2).

• Hepatic injuries: Ballooned hepatocytes (90.7%), apoptotic

(acidophil) bodies (90.7%).

Vo Thi Thu Trang et al (2018). 108 Military hospital

2nd

hit

Insulin

Resistance

3rd

hit

Normal

Liver Steatosis

NASH Fibrosis

The Metabolic

Syndrome

1st

hit

•Cytokines

•Adipokines

•Oxidative stress

•Others

Insulin Sensitizing Agents

Weight Loss

Antioxidants

Lipid Lowering Agents

Treatment of NASH

Farnesoid-X Receptor Agonist

Treatment: Weight Loss

Study N Intervention Duration

(months) Design ALT Histology

Hickman 31 Diet 15 Open label + N/A

Huang 16 Diet 12 Open label - +

Palmer 39 Diet 2-111 Case series + N/A

Andersen 41 Diet 4-23 Open label + +/-*

Kugelmas 8 Diet/Ex 3 Open label + N/A

Ueno 15 Diet/Ex 3 Open label + +

Zhu 34 Diet/Ex 12 Open label + N/A

Suzuki 348 Diet/Ex 12-24 Open label + N/A

Harrison 10 Orlistat Open label + +

Sabuncu 13/12 Sibutramine/Orlistat

6 Open label N/A

Luyckx 69 Surgery 27 Case series + +/-*

Silverman 91 Surgery 2-61 Case series + +

Kral 104 Surgery 41 Case series + +

Dixon 36 Surgery 26 Case series + +

Weight Loss Works

31 Patients

Randomized,

controlled trial

40% in

intervention

group lost 10%

body weight vs

0% in control

group

72% vs 30%

achieved study

endpoint

Promrat K, Hepatology 2010;51:121-129

Weight loss of ≥ 7% associated

with improvement in all

parameters of NASH except

fibrosis (need 10% for fibrosis)

Non-alcoholic fatty liver disease

Weight loss works

• 36 patients with obesity underwent paired liver biopsies at time

of laparoscopic gastric banding and 24 months later

• Mean weight loss 34 kg

• Histologic improvements in steatosis, inflammation, and

fibrosis

– Only 4 fulfilled criteria for NASH at second biopsy (24 at

entry)

– 18 had improvement in fibrosis by 2 stages

Dixon et al. Hepatology.2004:39(6):1647

Weight Loss Outcome Among Patients

Achieving Weight Loss Patients Sustaining

Weight Loss at 1 Yr[1]

≥ 10%[1]

Fibrosis

regression (45% of patients)[1]

< 10%

≥ 7%[1]

NASH resolution

(64% to 90% of patients)*

18%

≥ 5%[1-3]

Ballooning/inflammation improvement

(41% to 100% of patients)*

30%

≥ 3%[1-4] Steatosis improvement

(35% to 100% of patients*) Not reported

Percentage of Weight Loss Associated With

Histologic Improvement in NAFLD

1. Vilar-Gomez. Gastroenterology. 2015;149:367. 2. Promrat. Hepatology. 2010;51:121. 3. Harrison. Hepatology. 2009;49:80. 4. Wong. J Hepatol. 2013;59:536. Slide credit: clinicaloptions.com

*Depending on degree of weight loss.

Liver Histology After Gastric Bypass

0

5

10

15

20

25

30

Steatosis Inflammation Fibrosis Ballooning

Pre

Post

Hepatology 2004;39:1647-54

Nu

mb

er

1st biopsy 2nd biopsy at 8.5 months

Significant Improvement in histology

following bariatric surgery

Mattar SG et al. Annals of Surgery 2005; 242: 610-620

Lifestyle Modification Program

• Assessed benefits of dietician led lifestyle modification for

12 months

– Weekly meetings x 4 month, then monthly x 8

– Moderate carbohydrate, low fat, low glycemic index

• Emphasis on fruits and vegetables

– Exercise: moderate intensity for 30 minutes 3-5

days/week

• Increased to daily

• 154 Patients Enrolled

• Primary Endpoint

– Remission of NAFLD: IHTG of < 5% by MRS

• 64% in intervention group resolved NAFLD

• 20% in control group resolved NAFLD Wong VW, J Hepatol 2013

13

4150

60

97

0

20

40

60

80

100

<3.0% 3.0-4.9% 5.0-6.9% 7.0-9.9% ≥10.0%

Percentage of weight loss from baseline to month 12 n = 72 22 10 20 30 % p

ati

ents

wit

h r

esolu

tio

n o

f N

AF

LD

Degree of weight loss and resolution of

NAFLD by hepatic TG content

Wong VW, J Hepatol 2013

Exercise

• Optimal Intensity

– Goal is to maintain a lifestyle change

– Moderate exercise, burning ~400 kcal/session

– 3 times/week

– Improves insulin resistance

– Overall energy expenditure achieved per work-out more

important than intensity

» Training at 60% VO2max as effective as 80%

VO2max

– Weight loss

– Need to work out for longer period of time

Ryan AS, Aging Health, 2010

Treatment: Lipid Lowering Agents

Study Design (mts) Meds N ALT Hist

Laurin Open label (12) Clofibrate 16 - -

Basaranoglu RCT (1) Gemfibrozil 46 + NA

Horlander Open label (12) Atrovastatin 7 + +

Kiyici Open label (6) Atrovastatin 27 + NA

Hatzitolios Open label (6) Atrovastatin + NA

Gomez- Open label (12) Atrovastatin 25 + NA

Dominguez

Rallidis Open label (7) Pravastatin 5 + +/-

Merat RCT (6) Probucol 30 + NA

Statins are safe, improve ALT, not histology

Pioglitazone and Vitamin E

PIVENS Trial

Sanyal AJ, New Engl J Med 2010

%

Im

pro

vem

ent

Summary of PIVENS findings

• Vitamin E effective over placebo for NASH

• Pioglitazone improved, IR, ALT, steatosis and inflammation, but

not 1°outcome

• Only 34% (Pio) and 43% (Vit E) had histological response,

neither improved fibrosis

• Cannot generalize to diabetics or cirrhotics

• Different forms of Vitamin E

– Natural vs synthetic

• Confounders not controlled for:

– High dose Zn supplementation

– Use of concomitant vitamin A

– Smoking

• Trials not uniformly using Vit E as a treatment

• RCTs with no death excluded

Meta-analysis of Vitamin E – increased mortality?

Annals of Int Med, 2005

NO Pioglitazone for NASH

Pros

Improve2

•Insulin sensitivity •ALT •Steatosis •Inflammation •? Ballooning

Meta-analysis of 19 trials (16,390 patients) with T2DM, pioglitazone1 •Death, MI, or CVA: 4.4% of pioglitazone vs 5.7% of control (P = 0.005) •More CHF in pioglitazone (2.3%) vs control (1.8%) (P = .002), no effect on mortality

Cons

•Weight gain (2−4.7 kg) •Cardiac toxicity1

•Fracture risk2

•? Bladder cancer3

Abbreviations: ALT, alanine aminotransferase; CHF, congestive heart failure; CVA, cerebrovascular accident; MI, myocardial infarction; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus. 1. Lincoff AM, et al. JAMA. 2007;298:1180-1188. 2. Ratziu V. Nat Rev Gastroenterol Hepatol. 2013;10;646-685. 3. Lewis JD, et al. Diabetes Care. 2011;34:916-922. Courtesy of Mary Rinella, MD.

Obeticholic acid

• Semi-synthetic bile acid derivative

• Farnesoid-X Receptor (FXR) agonist

Adorini L, Drug Dis Today 2012;17:988-997

REGENERATE: Background

• NASH represents an important unmet medical need worldwide

– Increasing cause of liver-related morbidity and mortality[1,2]

– Anticipated to become principal indication for liver transplant in the United States by 2020[3]

– Currently lacks FDA-approved pharmacologic therapies[4]

• OCA: FXR agonist with preclinical activity against NASH[5]

– In randomized phase IIb FLINT study, OCA for 72 wks associated with improved fibrosis, other

histologic parameters in patients with noncirrhotic NASH[6]

– FDA designated OCA as a Breakthrough Therapy for patients with NASH and liver fibrosis

• Current report details 18-mo interim analysis of randomized phase III trial

comparing efficacy and safety of OCA at 2 doses vs placebo in patients with

NASH and liver fibrosis[7]

1. Angulo. Gastroenterology. 2015;149:389. 2. Younossi. Nat Rev Gastroenterol Hepatol. 2018;15:11. 3. Diehl. NEJM. 2017;377:2063. 4. FDA. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Draft guidance. December 2018. 5. Cipriani. J Lipid Res. 2010;51:771. 6. Neuschwander-Tetri. Lancet. 2015;385:956. 7. Younossi. EASL 2019. Abstr GS-06. Slide credit: clinicaloptions.com

REGENERATE: Study Design

• International, randomized, double-blind phase III study

Patients with biopsy-confirmed NASH; fibrosis stage 2/3*; NAFLD activity

score ≥ 4; total bilirubin ≤ 1.5 mg/dL; ALT < 10 x ULN; A1C ≤ 9.5%; no

cirrhosis, other chronic liver disease, or significant alcohol consumption†

(target N ~ 2400)

OCA 10 mg QD (n = 312)

Placebo QD (n = 311)

OCA 25 mg QD (n = 308)

Slide credit: clinicaloptions.com Younossi. EASL 2019. Abstr GS-06. Ratziu. EASL 2016. Abstr THU-488.

Mo 18 Interim Analysis (Histology)

Primary endpoint at interim analysis by paired biopsy: either fibrosis improvement by ≥ 1 stage without NASH worsening or NASH resolution without fibrosis worsening

*Exploratory cohort included those with fibrosis stage 1 and obesity, T2DM, or ALT > 1.5 x ULN. †Defined as > 2 units/day for women and 4 units/day for men for > 3 mos within 1 yr prior to screening.

Stratified by T2DM, treatment with thiazolidinediones or vitamin E

End of Study (Event driven)

REGENERATE: Baseline Characteristics

Baseline Characteristics OCA 10 mg (n = 312) OCA 25 mg (n = 308) Placebo (n = 311)

Mean age, yrs (SD) 55 (11) 55 (11) 55 (12)

Female, n (%) 177 (57) 175 (57) 187 (60)

White, n (%) 263 (92) 249 (87) 264 (94)

Hispanic ethnicity, n (%) 42 (15) 47 (17) 52 (18)

Fibrosis stage 3, n (%) 182 (58) 169 (55) 169 (54)

NAS ≥ 6, n (%) 211 (68) 208 (68) 215 (70)

Type 2 diabetes, n (%) 171 (55) 171 (56) 175 (56)

Mean ALT/AST, U/L (SD) 76 (47)/57 (34) 80 (56)/57 (34) 80 (57)/59 (41)

Concomitant medications, n (%) Lipid lowering

• Statins Antidiabetic medications

• Thiazolidinediones • Vitamin E

170 (54) 142 (46) 171 (55)

9 (3) 34 (11)

160 (52) 127 (41) 159 (52)

4 (1) 32 (10)

175 (56) 144 (46) 167 (54)

5 (2) 42 (14)

Slide credit: clinicaloptions.com Younossi. EASL 2019. Abstr GS-06.

REGENERATE Primary Endpoint:

Fibrosis Improvement

• Study met fibrosis primary endpoint at 18 mos (ITT)

Slide credit: clinicaloptions.com Younossi. EASL 2019. Abstr GS-06. Reproduced with permission.

Fibrosis Improvement by ≥ 1 Stage With No NASH Worsening

0

20

40

60

80

100

P = .04 P = .0002

11.9 17.6 23.1 Pat

ien

ts (

%)

Placebo OCA 10 mg OCA 25 mg

n =

• In PP population, OCA 25 mg

also associated with fibrosis

improvement across subgroups

defined by fibrosis stage, NAS score,

T2DM status

311 312 308

Glucagon-Like Peptide-1 Analogue:

Liraglutide

• GLP-1

– Controls serum glucose

• Induces insulin secretion

• Reduces glucagon

secretion

– Induces weight loss,

suppression of appetite and

delayed gastric emptying

Perazzo H, et al. Liver Int. 2016;Oct 11. [Epub ahead of print].

LEAN Study: Liraglutide in Overweight

NASH Patients Without Cirrhosis

Armstrong MJ, et al. Lancet. 2016;387:679-690.

Phase 2 (n=52) (UK, 4 sites)

Double-blind, placebo-controlled Histologic evidence of definite NASH (steatosis >5%, hepatocyte ballooning, lobular inflammation) Liver biopsy within 6 months of entry Stable type 2 diabetes allowed No Child-Pugh B/C cirrhosis

Week 0 48

Liraglutide 1.8 mg/day sc (n=26)

Placebo (n=26)

LEAN: Liraglutide Efficacy and Action in NASH. Patients stratified by diabetes status. Primary endpoint (week 72, ITT): Improvement in liver histology without worsening of fibrosis. Improvement: disappearance of hepatocellular ballooning. Worsening of fibrosis: any increase in Kleiner fibrosis stage.

Week 0 48

Armstrong MJ, et al. Lancet. 2016;387:679-690. Armstrong MJ, et al. Lancet. 2016;387:679-690.

© 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG

Fibroblast Growth Factor 21 (FGF21)

Phase 2 Double-Blind, Placebo-Controlled Study

• Key Eligibility Criteria: biopsy-proven NASH with fibrosis stage 1-3 (within 1 year of

screening), BMI >25 kg/m2, hepatic fat fraction ≥ 10% (MRI-PDFF)

• Primary Efficacy Endpoint: change in hepatic fat fraction (%) from baseline to Week 16

• Key Exploratory Endpoints: adiponectin, lipids, ALT, AST, MRE, and serum Pro-C3

• Safety Assessments: AEs, laboratory parameters, and vital signs

Week 16 Week 20

Placeb

o lead-

in

period

Week -1 Baseline

BMS-986036 SC

(20 mg QW)

BMS-986036 SC

(10 mg QD)

Placebo SC

(QD)

Follow

-up

period

Randomization 1:1:1

Stratified by T2DM

n = 25*

n = 24*

n = 26*

*Planned sample size was 30 per group; enrollment ended early due to the significant effect of

BMS-986036 on the primary endpoint seen during preplanned interim analysis at treatment Week 8. Sanyal et al. BMS. Abstract 182

FGF2:Associated with increased insulin sensitivity, decreased lipogenesis,

improvement in lipids, and antifibrotic effects

Improvement in ALT, Fat, And Stiffness

Examples of NASH Treatments in

Phase II or III Investigations

Steatohepatitis (NASH) Cirrhosis Normal Liver Steatosis (NAFL)

Targets related to insulin resistance

and/or lipid metabolism

Targets related to lipotoxicity and oxidative stress

Targets related to inflammation and immune activation

Targets related to cell death

(apoptosis and necrosis)

Targets related to fibrogenesis and

collagen turnover

PPARγ: Pioglitazone GLP-1: Liraglutide,

semaglutide ACC: GS-0976,PF-05221304 SCD1: Aramchol FGF21: BMS-986036 THR-β: MGL-3196, VK2809

Galectin: GR-MD-02

NAFLD

Bold = phase III Some agents have multiple targets

PPARα/∂: Elafibranor PPARα/∂/γ: Lanifibranor FXR: OCA,

GS-9674, tropifexor

FGF19: NGM282 MPC: MSDC-0602K Slide credit: clinicaloptions.com

CCR2/5: Cenicriviroc (inflammatory target but affects fibrosis)

ASK1: Selonsertib (cell death target but affects fibrosis) Caspase: Emricasan P2X7R: SGM-1019

Lots of Trials for NAFLD Actively Enrolling

Feasibility and effectiveness of web-based vs. standard counselling programmes for NAFLD

*Funded by FP7-HEALTH 2009-13 241762 contract; †Associated with improvement in NAFLD histology in other studies

Mazzotti A, et al. ILC 2018, PS-112

Methods

• Multidisciplinary, 5-week, group-based lifestyle

modification programme aimed at healthy diet and

habitual physical activity (Italy, 2010 to 2015)*

• 716 patients with NAFLD

• Equal treatment provided for comorbidities,

but no specific therapy for liver disease

• Routine observations every 6 months

Results

• Baseline: Mean ± SD age, 52 ± 13; similar BMI

(33 kg/m2); more males (67% vs. 45%), younger

age and higher education in WC

• Attrition higher in WC (OR 2.46)

• Primary outcome: 10% weight loss target†

achieved in WC 8.6% v.s GC 10% (NS; ITT)

• BMI decreased similarly; weight loss accompanied

by calorie intake and physical activity

• Liver enzymes and surrogate markers of steatosis

and fibrosis improved similarly in both groups

Conclusion: Structured web-based intervention as

effective as group-counselling in achieving 10% weight

loss in motivated patients

• Standard programme (Group Cohort, GC) (N=438; completed within 3 months)

• Web-based intervention (Web Cohort, WC) (N=278; designed for people who could not enter GC

because of logistical, job or time constraints;

included 5 modules with interactive games, offline

contact with centre, and questionnaires to investigate

motivation, competence, and learning)

Months

ANOVA: Time, p<0.001

Time x treatment, NS

-7

-6

-5

-4

-3

-2

-1

0

0 6 12 24

WC GC

Weig

ht lo

ss (

%)

Patients, n/N (%)

GC – 28/383 (7) 38/352 (11) 44/301 (15)

WC – 11/211 (5) 21/160 (13) 24/118 (20)

• Conclusions The accuracy of noninvasive criteria in non-obese patients is worse

further validation is required and caution is suggested in interpretation of this result

Noninvasive prediction of oesophageal varices by LSM and platelet values in patients with liver cirrhosis due to NAFLD

*Histology and/or LSM >11.5 KPa for M and >11 KPa for XL probe; †Similar results in patients with LSM ≥13 KPa and considering each centre separately

Petta S, et al. ILC 2018, PS-177

• Aim To validate the noninvasive Baveno VI (LS <20 and PLT >150,000) and extended Baveno VI (LSM <25 and

PLT >110,000) criteria in patients with compensated cirrhosis due to NAFLD to screen for varices, and the potential

differences in LSM from M and XL probes

• Methods Multicentre, cross-sectional study. Retrospective review of 790 patients prospectively recruited at first

diagnosis of NAFLD-related compensated Child–Pugh A cirrhosis* and with LSM by FibroScan (M or XL probes),

endocopy (OGD) evaluation of Ovs, and OVs needing of treatment (OVNT)

• Results n=314 had LSM by both M and XL probe (Training set); n=339 by only M probe (Validation set);

n=138 by only XL probe (Validation set)

34

1

10

33

4

14

58

4

13

54

4

17

69

4

14

62

5

18

0

25

50

75

100

Spared OGD

Missed OVNT

Missed small OV

Spared OGD

Missed OVNT

Missed small OV

Baveno VI Expanded Baveno VI NAFLD Cirrhosis Criteria

Training set

(n=314)

Validation set

(n=338)

Pa

tie

nts

(%

)

NAFLD cirrhosis criteria:

PLT >110,000 and LSM <30 KPa for M probe†

65

5 13

46

2

16

0

25

50

75

100

Spared OGD

Missed OVNT

Missed small OV

Spared OGD

Missed OVNT

Missed small OV

NAFLD Cirrhosis Criteria

Training set

(n=314) Validation set

(n=338)

Pa

tie

nts

(%

)

NAFLD cirrhosis criteria:

PLT >110,000 and LSM <25 KPa for XL probe†

Frequency and outcomes of liver transplantation for NASH in Europe

*Multivariable Cox regression; adjusted for donor and recipient factors

Haldar D, et al. ILC 2018, PS-041

Aim: To describe the changing frequency of LTx

for NASH in Europe, determine clinical outcomes

and prognostic factors

Methods

• Retrospective cohort analysis of 68,950 adult

patients who underwent primary LTx for chronic

liver disease between 01/01/2002 and 31/12/2016

using the ELTR database; data prospectively

collected from 174 centres in 33 countries

Conclusions

• The proportion of LTxs performed for patients with

NASH has risen more than for any other indication

• Significantly higher proportion of NASH recipients

with concomitant HCC than for other indications.

• NASH is not an independent predictor of post-LTx

patient or graft survival

• Amongst NASH recipients, older age, higher MELD

and extremes of BMI carry a post-LTx mortality

risk, can aid risk stratification and careful

selection of patients with NASH for LTx

Results

• Changing indications for LTx

– Primary indication was NASH (2,741 [4%] pts)

– proportion of LTx performed for patients with NASH: 1.2%

(2002) 8.4% (2016)

– ARLD was the most common indication (n=22,226; 32.3%)

• Recipient differences

• Patient and graft outcomes after LTx

– NASH not an independent predictor of post-LTx patient survival*

• Key determinants of post-LT survival in NASH recipients

NASH Non-NASH

Age years; (IQR) 60 (54–64) 55 (48–61)

BMI kg/m–2 (SD) 32.6 (4.57) 25.8 (4.45)

HCC (%) 39.1 28.9

For patient survival For graft survival

HR 1.06 (0.97–1.17) 0.90 (0.79–1.04)

For recipients without HCC HR

Recipient age (years)

61–65

>65

1.96 (1.29–2.98)

1.77 (1.11–2.82)

MELD >23 1.54 (1.04–2.30)

Recipient BMI (kg/m2)

<18.5

18.5–25

>40

5.04 (1.18–21.56)

2.34 (1.28–4.26)

2.24 (1.30–3.87)

Donor blood group B 0.41 (0.23–0.72)

Exposure database HR (95% CI)

NAFLD/NASH

HSD

IPCI

SIDIAP

THIN

Subtotal (I-squared=92.0%, p=0.000)

1.63 (1.00, 2.65)

7.92 (4.02, 15.57)

2.11 (1.59, 2.80)

6.07 (4.38, 8.43)

3.51 (1.72, 7.16)

NAFLD

SIDIAP

THIN

Subtotal (I-squared=94.8%, p=0.000)

1.90 (1.39, 2.58)

5.26 (3.76, 7.36)

3.15 (1.16, 8.56)

NASH

SIDIAP

THIN

Subtotal (I-squared=0.0%, p=0.506)

6.99 (3.18, 15.38)

11.75 (3.16, 43.64)

8.02 (4.08, 15.77)

NAFLD and risk of incident NASH, cirrhosis and HCC in 18 million European electronic healthcare records

HR values adjusted for age, smoking status and BMI

Alexander M, et al. ILC 2018, PS-106

• 134,854 NAFLD or NASH patients

– From Italy, Spain, the Netherlands, and UK

• Matching 100:1 by practice site, gender, age ±5 years, and visit

• Mean follow-up 3.5 years (>500,000 person years)

Association with cirrhosis Association with HCC

Exposure database HR (95% CI)

NAFLD/NASH

HSD

IPCI

SIDIAP

THIN

Subtotal (I-squared=96.6%, p=0.000)

2.45 (1.68, 3.58)

5.20 (3.60, 7.42)

3.62 (3.03, 4.32)

10.47 (8.76, 12.52)

4.73 (2.43, 9.19)

NAFLD

SIDIAP

THIN

Subtotal (I-squared=98.6%, p=0.000)

3.26 (2.70, 3.94)

10.40 (8.62, 12.54)

5.83 (1.87, 18.13)

NASH

SIDIAP

THIN

Subtotal (I-squared=90.2%, p=0.001)

11.56 (6.63, 20.15)

45.19 (24.14, 84.59)

22.67 (5.96, 86.23)

128 64 32 16 8 4 2 1 .6

HR (95% CI) 64 32 16 8 4 2 1 .6

HR (95% CI)

Summary

• NAFLD is part of a systemic inflammatory process and other

diseases (cardiovascular) are associated

• More prevalent than previously estimated

– Hispanics and diabetics at particular risk

• Biopsy is required for research studies not practical in clinical

practice, steatosis benign from hepatic point of view, NASH

can progress to cirrhosis

• Smoking and excess alcohol are bad, but coffee and sleep

likely good

Summary

• Weight loss goal of 10% is best for immediate first level histopathology

improvement

• Moderate exercise may not be enough to effect change in NASH. Vigorous

exercise for >150 min/week ideal

• Vitamin E may be considered for patients with proven NASH with caveats

(use natural Vit E)

• Statins are safe and effective for lipid disorders, not NASH

• Bariatric surgery is an expensive solution

• Dietician visits for all patients

• Consider weight loss contract

• Fructose free diet

• Vegetarian diet preferred

• Mediterranean diet optimal