non-alcoholic fatty liver disease (nafld): pathogenesis
TRANSCRIPT
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