NASH: State of the Science

Epidemiology, Pathophysiology, and Natural

History
Quentin M. Anstee, BSc, MB BS, PhD,
MRCP(UK), FRCP
Professor of Experimental Hepatology
Consultant Hepatologist
Institute of Cellular Medicine
Newcastle University
Newcastle Upon Tyne, United Kingdom
This program is supported by an educational grant from
Gilead Sciences, Inc.
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Faculty Disclosure
Quentin M. Anstee, BSc, MB BS, PhD, MRCP(UK), FRCP, has disclosed that he
has received consulting fees paid to his institution from Abbott, Acuitas Medical,
Allergan/Tobira, E3Bio, Galmed, Genfit SA, Gilead Sciences, Grunenthal, Imperial
Innovations, Intercept Pharma Europe Ltd., Inventiva, Janssen, Kenes, Lilly,
MedImmune, NewGene, Novartis, Pfizer, and Raptor Pharma; funds for research
support paid to his institution from AbbVie, Allergan/Tobira, AstraZeneca,
GlaxoSmithKline, Novartis, and Vertex; active research collaborations (including
the EU H2020 EPoS & EU IMI2 LITMUS Consortia*) AbbVie, Antaros Medical,*
Allergan/Tobira, AstraZeneca, Boehringer Ingelheim,* Ellegaard Gottingen
Minipigs AS,* Exalenz Bioscience,* Genfit SA,* GlaxoSmithKline, Intercept
Pharma Europe,* iXscient,* Lilly,* Nordic Bioscience,* Novartis,* Novo Nordisk
A/S,* One Way Liver Genomics SL,* Perspectum Diagnostics,* Pfizer,* sanofi-
aventis Deutschland,* SomaLogic,* and Takeda Pharmaceuticals International*;
and speaking fees for Abbott, Allergan/Tobira, Falk, Genfit SA, Gilead Sciences,
and Intercept Pharma.
Outline
 Epidemiology
 Pathogenesis of NAFLD
– Role of obesity and insulin resistance as pathogenic drivers
– Factors leading to hepatocellular injury
– Oxidative stress, lipotoxicity, mitochondrial dysfunction, inflammatory
activation and production of cytokines and adipokines, gut dysbiosis,
and ER stress
 Natural History
 Diagnostic Strategies
 A “Right-Shift” in Population Body Weight
UK Distribution of BMI in Adults Aged ≥ 18 Yrs (Population Weighted)
Underweight Healthy Overweight Obese Severely obese
weight
Men, 1991-1993
Men, 2011-2013
Proportion of population

Women, 1991-1993
Women, 2011-2013

Men
14.6%
24.8%
Men Women
0.7% 16.4% Men
Men Men 0.3%
0.9% 22.8%
37.8% 46.7% 1.7%
Women
28.4% 44.3% Women
1.3%
Women Women 1.4%
1.8%
47.6% 33.3% 3.7%
38.2% 33.6%

12 18.5 30 25 40 50
BMI (kg/m2)
Public Health England. Patterns and trends in adult obesity. April 2016. Slide credit: clinicaloptions.com
 Prevalence of NAFLD in the General Population

In a US population sample (n = 328)[1]: Rising Obesity Prevalence Correlates With

 NAFLD by ultrasound 46% Rising Prevalence of NAFLD[4]
 NASH 12.2% (29.9% of those with 35
NAFLD)

Prevalence of NAFLD (%)

30 Israel USA

In the Dionysos study, NAFLD present in[2]: 25

Korea
 Obese pts (BMI > 30), 94% 20 Taiwan
 Overweight pts (BMI > 25), 67% India
China Japan Mexico
 Normal weight pts, 25% 15
10 Italy
In apparently healthy living liver donors,
5
histological NASH in[3]:
 Europe, 3% to 16% 0
 USA, 6% to 15% 0 5 10 15 20 25 30 35
Prevalence of Obesity (%)
1. Williams CD, et al. Gastro. 2011;140:124-31.
2. Bellentani S, et al. E J Gastro Hep. 2004; 1087-1093. 3. Anstee et al. Nat Rev Gastroenterol Hepatol.
2013;10:330-344. 4. Loomba R, et al. Nat Rev Gastroenterol Hepatol. 2013;10:686-690. Slide credit: clinicaloptions.com
 The Spectrum of NAFLD

Steatosis (NAFL)

Steatohepatitis (NASH)

Fibrosis

Cirrhosis

HCC

Slide credit: clinicaloptions.com

The Spectrum of NAFLD: Steatosis

Steatosis (NAFL)
Fat infiltration > 5%
± mild inflammation

Slide credit: clinicaloptions.com

 The Spectrum of NAFLD: Steatohepatitis

Steatosis (NAFL) Steatosis +

necroinflammation (eg,
ballooning, Mallory bodies,
megamitochondria)

Steatohepatitis (NASH)

Slide credit: clinicaloptions.com

 The Spectrum of NAFLD: Fibrosis/Cirrhosis to HCC

Steatosis (NAFL) Increasing fibrosis,

eventually leading to
cirrhosis

Steatohepatitis (NASH)

Fibrosis

Cirrhosis

HCC

Slide credit: clinicaloptions.com

 NAFLD-Associated HCC
 Increasing proportion of NAFLD-associated HCC in England between 2000 and 2010
Underlying Liver Diseases in HCC Cases
120
No CLD
Transplantation Rate (%)

100 ALD
NAFLD
HCV
80 HBV
Haem
60 Crypt
AIH
PBC
40 Other

20

0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Yr
Dyson J, et al. J Hepatol. 2014;60:110-117. Slide credit: clinicaloptions.com
 NAFLD: Major Indication for Liver
Transplantation
 Retrospective cohort study of the Ohio Solid Organ Transplantation Consortium database (N = 2356)
 From 2000-2012, obesity rate increased from 21.5% to 30.1%, proportion of transplanted pts with
NASH increased from 0% to 23.4%
Transplantation Rate in Ohio by Diagnosis
80
Transplantation Rate (%)

60 Diagnosis at Time of Listing

HCV infection
40 Alcoholic cirrhosis
NASH
20

00 01 02 03 04 05 06 07 08 09 10 11 12
20 20 20 20 20 20 20 20 20 20 20 20 20
Quillin RC 3rd, et al. Surgery. 2014;156:1049-1056. Yr Slide credit: clinicaloptions.com
 NASH: Number One Indication for Liver
Transplant in Pts Aged < 50 Yrs
 In 2015 registry of pts listed for liver transplant, NASH surpassed
HCV infection
Etiology Among Pts Listed for Liver Transplant
NASH and cryptogenic cirrhosis P < .0001
HCV infection 150
194 124
200
100
Pts Aged 35-49 Yrs

From 2002-2014 (%)

Change in Etiology
160 148
50
120 25
80 0
-25
40
-50
0 -78
NASH and HCV -100
Cryptogenic Infection
Cirrhosis -150
Banini BA, et al. ACG 2016. Abstract 46. Slide credit: clinicaloptions.com
Outline
 Epidemiology
 Pathogenesis of NAFLD
– Role of obesity and insulin resistance as pathogenic drivers
– Factors leading to hepatocellular injury
– Oxidative stress, lipotoxicity, mitochondrial dysfunction, inflammatory
activation and production of cytokines and adipokines, gut dysbiosis,
and ER stress
 Natural History
 Diagnostic Strategies
Obesity and Insulin Resistance as Pathogenic
Drivers
Central
Obesity
Thrombophilia Hypertension

Macrovascular Insulin Hyperuricemia

Disease Resistance

Hyperglycemia Dyslipidemia

NAFLD
Slide credit: clinicaloptions.com
 Relationship Between Liver Fat and Metabolic
Syndrome
 Nondiabetic subjects (N = 271)
 Presence of all components of metabolic syndrome correlated
with liver fat content by 1H-MRS
 Liver fat content significantly increased in pts with metabolic
syndrome vs those without
 This association is independent of age, sex, BMI

Kotronen A, et al. J Clin Endocrinol Metab. 2007;92:3490-3497. Slide credit: clinicaloptions.com

NAFLD as a Complex Disease Trait: Genetic and
Environmental Modifiers
Environment
Normal Sedentary lifestyle
Snacking, fast food
Saturated fats
Trans fats
Processed red meat
Steatosis

NASH

Genes
PNPLA3
TM6SF2
GCKR
Cirrhosis
SOD2
MBOAT7
Slide credit: clinicaloptions.com
 Targeting Pathophysiological Processes
Normal Liver NAFL NASH Cirrhosis

Targets related to Targets related to

Targets related to Targets related to Targets related to
insulin resistance cell death
lipotoxicity and inflammation and fibrogenesis and
and/or lipid (apoptosis and
oxidative stress immune activation collagen turnover
metabolism necrosis)

PPARγ: Pioglitazone PPARα/∂: Elafibranor CCR2/5: ASK1: Selonsertib LOXL2: Simtuzumab

GLP-1: Liraglutide, PPARα/∂/γ: IVA337 C Caspases: Emricasan Galectin: GR-MD-02
Semaglutide PPARα/γ: Saroglitazar e
ACC: GS-0976, mTOT: MSDC-0602K ni
PF-05221304 FXR: OCA, GS-9674, cr
SCD1: Aramchol LJN-452, LMB-763 ivi
SGLT1/2: LIK066 TGR5: INT-767, INT-777 ro
FGF21: BMS-986036 ASBT: Volixibat c
THR-β: MGL-3196 FGF19: NGM282 AOC3: BI
Vitamin E 1
4
 Nuclear Receptors
 Ligand-dependent transcription factors
 Modulate hepatic metabolism of glucose and lipids
 NR1 subfamily particularly important in pts with NAFLD

RXRα

PPARα/β/γ LXRα/β FXRα CAR PXR

Nuclear Receptor Heterodimers

Caligiuri A, et al. Int J Mol Sci. 2016;17:1575. Slide credit: clinicaloptions.com

 Nuclear Receptors “Fine-Tune” Metabolism
 Farnesoid X receptor (FXR):  Peroxisome proliferator activated
modulates crosstalk between bile receptors (PPARs): integrate
acid transport/signaling and lipid/glucose metabolism, energy
hepatic lipid metabolism[1] homeostasis, inflammation[2]
 Exploitable drug targets  Exploitable drug targets
– FXR agonists: OCA, GS-9674, – PPARγ agonist: pioglitazone
LJN-452, LMB-763
– PPARα/∂ agonist: elafibranor
– TGR5 agonists: INT-767, INT-777
– PPARα/∂/γ agonist: IVA337
– ASBT inhibitor: SHP-626
– PPARα/γ agonist: saroglitazar
– FGF-19 agonist: NGM-282

1. Evans RM, et al. Cell. 2014;157:255-266. 2. Gross B, et al. Nat Rev Endocrinol. 2017;13:36-49. Slide credit: clinicaloptions.com
Outline
 Epidemiology
 Pathogenesis of NAFLD
– Role of obesity and insulin resistance as pathogenic drivers
– Factors leading to hepatocellular injury
– Oxidative stress, lipotoxicity, mitochondrial dysfunction, inflammatory
activation and production of cytokines and adipokines, gut dysbiosis,
and ER stress
 Natural History
 Diagnostic Strategies
 NAFLD Natural History
25% to 35% of general population has NAFLD Only a minority will ever progress beyond NAFL

An important paradox exists:

A substantial proportion of the population has NAFLD but only a minority progresses
to advanced liver disease or morbidity/mortality

Fazel Y, et al. Metabolism. 2016;65:1017-1025. Slide credit: clinicaloptions.com

NAFLD Natural History

How does NAFLD progress?

Serial biopsy studies

What histologic features predict that pts will experience

significant events or reach clinically relevant endpoints?

Long-term prospective
follow-up studies

Slide credit: clinicaloptions.com

 Progression of Fibrosis in Pts With NAFL vs NASH
 Meta-analysis of 11 paired-biopsy studies (N = 411) with 2145.5 person-years of follow-up
NAFL (n = 150) NASH (n = 261)
Study Effect Size (95% CI) Study Effect Size (95% CI)

From Western population From Western population

Teli 0.01 (-0.01 to 0.03) Evans 0.09 (-0.01 to 0.19)
Ekstedt 0.06 (0.04 to 0.08) Fassio 0.25 (0.04 to 0.46)
Pais 0.19 (0.06 to 0.31) Subtotal (I-squared = 44.0%; P = .182) 0.14 (0 to 0.29)
Subtotal (I-squared = 87.0%; 0.05 (0 to 0.10)
P = .000)
From Eastern population
From Eastern population 0.15 (0.06 to 0.24) Wong 0.28 (0.07 to 0.49)
Wong Hui
0.06 (-0.05 to 0.16) 0.12 (0.03 to 0.21)
Hui Subtotal (I-squared = 44.8%; P = .179)
0.11 (0 to 0.20) 0.17 (0.03 to 0.31)
Subtotal (I-squared = 44.3%; P = .000) Overall (I-squared = 21.1%; P = .283)
0.07 (0.02 to 0.11) 0.14 (0.07 to 0.21)
Overall (I-squared = 81.2%; P = .000)

0 0.1 0.2 0 0.1 0.2 0.3

39.1% (52/133) had fibrosis progression 34.5% (40/116) had fibrosis progression
0.07 stages/yr (95% CI: 0.02-0.11) 0.14 stages/yr (95% CI: 0.07-0.21)
1 stage in 14.3 yrs (95% CI: 9.1-50.0) 1 stage in 7.1 yrs (95% CI: 4.8-14.3)

Singh S, et al. Clin Gastroenterol Hepatol. 2015;13:643-654. Slide credit: clinicaloptions.com

 NAFLD Progression From Steatosis to Fibrosing
Steatohepatitis
 Analysis of N = 108 NAFLD pts with serial biopsies
Baseline Follow-up

Median interval
between biopsies: 6.6 yrs F3
(range: 1.3-22.6) Stable
Progression

F4
Regression

Median Fibrosis
NAFL follow-up: 8 yrs Progression
Progression Predictor of
n = 27 (range: 1.7-22.6) n = 10 (37%)
to NASH Progression:
n = 12 (44%)
Progression T2DM
to F3
n = 6 (22%)
McPherson S, et al. J Hepatol. 2015;62:1148-1155. Slide credit: clinicaloptions.com
 Subsets of Pts With Different Fibrosis
Progression Rates
 Meta-analysis of 11 paired-biopsy studies
100

Pts With Progression From F0 (%)

83 82
79 Progression From F0
80 After Mean 5.9 ± 3.7 Yrs of Follow-up
Slow progression (to F1/2)
Rapid progression (to F/4)
60

40

21 18
20 17

n= 41 11 24 5 9 2
0
NAFLD NAFL NASH
Singh S, et al. Clin Gastroenterol Hepatol. 2015;13:643-654. Slide credit: clinicaloptions.com
 Fibrosis Stage, Not Presence of Steatohepatitis,
Strongest Predictor of NAFLD-Related Mortality
 Cohort study of pts in Sweden with NAFLD (N = 229) followed for a mean of
26.4 ± 5.6 yrs
Survival by NAS and Fibrosis Stage Survival by Fibrosis Stage
Pts with NAS 5-8 and fibrosis stage 0-2 Pts with fibrosis stage 0-2
Pts with NAS 0-4 and fibrosis stage 3-4 Pts with fibrosis stage 3-4
1.00 Reference population 1.00 Reference population

0.75 0.75

Survival
Survival

0.50 0.50

0.25 0.25
Log-rank test: P = .17 Log-rank test: P < .001
0 0
0 10 20 30 0 10 20 30
Yrs Yrs
Ekstedt M, et al. Hepatology. 2015;61:1547-1554. Slide credit: clinicaloptions.com
 PRELHIN Study: Liver Fibrosis Associated With
Long-term Outcomes in Pts With NAFLD
 Retrospective analysis in pts with NAFLD (N = 619); median follow-up: 12.6
yrs (range: 0.3-35.1) Multivariate Analysis of Long-term
1.0 Outcomes by Fibrosis Stage
Cumulative Survival (%)

100

HR Relative to Stage F0
0.8 Death/OLT
80
P = .238 Liver-related complications
0.6
Non-NASH, Fib (-) 60
0.4 Non-NASH, Fib (+) P = .800
NASH, Fib (-) 40
0.2 NASH, Fib (+)
20
Censored
0
0
0 5 10 15 20 F1 F2 F3 F4
Follow-up (Yrs)
Only fibrosis stage was associated with overall mortality, OLT, and liver-related events.
Presence of NASH, NAS (or any of its components) had no independent prognostic effect.
Angulo P, et al. Gastroenterology. 2015;149:389-397. Slide credit: clinicaloptions.com
Outline
 Epidemiology
 Pathogenesis of NAFLD
– Role of obesity and insulin resistance as pathogenic drivers
– Factors leading to hepatocellular injury
– Oxidative stress, lipotoxicity, mitochondrial dysfunction, inflammatory
activation and production of cytokines and adipokines, gut dysbiosis,
and ER stress
 Natural History
 Diagnostic Strategies
NAFLD and NASH . . . Finding the “At-Risk” Pt

?
Is this steatosis or How much fibrosis
steatohepatitis? is there?
 NAFLD Presentation
 Symptoms  Common scenarios
– Usually asymptomatic, majority – Statin monitoring
discovered by chance
– “Annual reviews” in T2DM/lipid/
– Fatigue frequently present hypertension clinics
 Often an “incidental finding” – Medical insurance/occupational
health checks
– Incidental abnormal LFTs
– Incidental “bright liver” on
imaging
– Incidental hepatomegaly

De Alwis NM, et al. Dig Dis. 2016;34:19-26. Slide credit: clinicaloptions.com

 Routine Clinical Biochemistry (LFTs)?
 NAFLD the most common diagnosis in pts with “incidental”
abnormal LFTs[1-3]
 Liver enzymes may be normal in ~ 80% of NAFLD pts[4,5]
– Transaminases are not a sensitive test for NAFLD/NASH
– Poor correlation between ALT and histology
– ALT typically decreases with advanced fibrosis
– As NASH progresses, ALT/AST ratio may reverse to ALT < AST
 Severity of histology in NAFLD similar for pts with normal vs
abnormal LFTs[6-8]
References in slidenotes. Slide credit: clinicaloptions.com
 Clinical Predictors of NASH in Pts With NAFLD

Characteristic Outcome
Advanced age[1] Greater duration of disease
Sex[2] Postmenopausal women experience accelerated disease
↑ Prevalence, severity in Hispanic, Asian pts;
Race[3,4]
↓ prevalence, severity in black pts
HTN, central obesity, Risk increases with metabolic syndrome,* 66%
dyslipidemia (↑ TG, ↓ HDL), prevalence of bridging fibrosis if older than 50 yrs of age
insulin resistance/diabetes[5] and obese or diabetic[6,7]
AST/ALT ratio > 1,[8]
Indicators of advanced fibrosis/cirrhosis in NASH
low platelets[9]
Can be associated with greater risk of disease
Persistently elevated ALT[10]
progression
*Strongest predictors of advanced disease, regardless of liver enzyme elevation.
*Based on ATP III criteria.
References in slidenotes. Slide credit: clinicaloptions.com
 Fibrosis Assessment for Pts With NAFLD

Category Blood Tests Assessing Fibrosis Stage in NAFLD

 NAFLD fibrosis score  AST/ALT ratio
 FIB-4 score  BARD
“Simple” lab/clinical indices[6-10]
 Ferritin levels  APRI
 IgA levels  BAAT
 FibroTest†
“Expanded” lab indices [4,5]
 FibroMeter
 ELF test*
Direct fibrosis markers[1-3]
 PIIINP
*Assays HA, PIIINP, and TIMP-1; F3/4 fibrosis, AUC: 0.90 (95% CI: 0.84-0.96).
†
Includes total bilirubin, GGT, α2-macroglobulin, ApoA1, and haptoglobin, corrected for age and sex; F3/4 fibrosis,
AUC: 0.88 (95% CI: 0.82-0.92).

Routine LFTs do not differentiate NAFL vs NASH or accurately stage fibrosis

References in slidenotes. Slide credit: clinicaloptions.com

 Simple Scores for Assessing Presence of Advanced
(F3/4) Fibrosis
Parameter
Age
AST FIB-4
NAFLD Score
ALT
Fibrosis
Platelet count
Score
BMI
NAFLD Albumin FIB-4
Effect NPV or PPV, %
Fibrosis Effect NPV or PPV, % Score[2,3]
Score[1] Impaired fasting glucose/diabetes?
Rules out
< 1.3 95
Rules out fibrosis
< -1.455 88 to 93
fibrosis
Predicts
> 3.25 75
Predicts fibrosis
> 0.676 82 to 90
fibrosis
Low Cutoff High Cutoff
(NPV) (PPV)

Low Probability of F3/4 Indeterminate High Probability of F3/4

1. Angulo P, et al. Hepatology. 2007;45:846-854. 2. Sterling RK, et al. Hepatology. 2006;43:1317-1325.

3. McPherson S, et al. Gut. 2010;59:1265-1269.  Slide credit: clinicaloptions.com
 Comparison of the Diagnostic Performance of
Simple Tests for Advanced Fibrosis
 Study comparing identification of F3/4 in pts with NAFLD (N = 145)
Test AUC (95% CI) Cutoff Sens, % Spec, % PPV, % NPV, %
AST/ALT 0.83 0.8 74 78 44 93
ratio (0.74-0.91) 1 52 90 55 89
0.67
APRI 1 27 89 37 84
(0.54-0.8)
0.77
BARD score 2 89 44 27 95
(0.68-0.87)
0.86 1.30 85 65 36 95
FIB-4 score
(0.78-0.94) 3.25 26 98 75 85
NAFLD 0.81 -1.455 78 58 30 92
fibrosis score (0.71-0.91) 0.676 33 98 79 86

McPherson S, et al. Gut. 2010;59:1265-1269. Slide credit: clinicaloptions.com

The Challenge of Indeterminate Results
Avoid biopsy below Avoid biopsy above
lower threshold upper threshold
(True Negative + False Negative) (True Positive + False Positive)
TN FN TP FP

False negatives False positives

Normal Diseased

Low Cutoff High Cutoff

(NPV) (PPV)

Low Probability of F3/4 Indeterminate High Probability of F3/4

Slide credit: clinicaloptions.com
 Age as a Confounder for Accurate Diagnosis of
Advanced Fibrosis in NAFLD: Clinical Indices
 Pts with NAFLD in European specialist hepatology clinics (N = 634)
NAFLD Fibrosis Score (5-Yr Intervals) FIB-4 (5-Yr Intervals)
150 150
Sensitivity – 1.455 Sensitivity – 1.3
Sensitivity/Specificity (%)

Sensitivity/Specificity (%)
Specificity – 1.455 Specificity – 1.3

100 100

50 50

0 0
35 -40 -45 -50 -55 -60 -65 65 35 -40 -45 -50 -55 60 65 65
< 35 40 45 50 55 60 > < 35 40 45 50 55- 60- >
Age (Yrs) Age (Yrs)
McPherson S, et al. Am J Gastroenterol. 2017;112:740-751. Slide credit: clinicaloptions.com
 Age as a Confounder for Accurate Diagnosis of
Advanced Fibrosis in NAFLD: ALT and AST
 Pts with NAFLD in European specialist hepatology clinics (N = 634)
ALT AST
Stage F0-F1 Fibrosis Stage F2-F4 Fibrosis Stage F0-F1 Fibrosis Stage F2-F4 Fibrosis
150 150 100 100

Mean AST (IU/L)

125 125
Mean ALT I(U/L)

80 80
100 100
60 60
75 75
40 40
50 50
25 25 20 20
0 0 0 0
36 45 55 64 64 6 5 5 4 64 6 5 5 4 64 6 45 55 64 64
< 36- 46- 55- > < 3 36-4 46-5 55-6 > < 3 36-4 46-5 55-6 > 3
< 36- 46- 55- >
Age Age Age Age

McPherson S, et al. Am J Gastroenterol. 2017;112:740-751. Slide credit: clinicaloptions.com

 Excluding Advanced Fibrosis in Older Pts
Age-Specific Use of NAFLD Fibrosis Score NAFLD Fibrosis
Suspected NAFLD Threshold Score FIB-4
Performance in
Pts > 65 Yrs of
Age Current New Current New

≤ 35 yrs 35-65 yrs ≥ 65 yrs

Cutoff -1.455 0.12 1.3 2.0
Existing thresholds used New thresholds used Sensitivity, % 93 80 93 77
Specificity, % 20 70 35 70
< -1.455 -1.455 > 0.676 < 0.12 0.12- > 0.676 Pts definitively
to 0.676 0.676 classified as high 45 80 55 82
or low risk, %
Advanced Advanced
Pts correctly
fibrosis fibrosis Further
classified by
excluded likely investigation 76 80 78 78
histological stage,
%
Alternative Further Advanced Advanced
fibrosis investigation fibrosis fibrosis
assessment excluded likely

McPherson S, et al. Am J Gastroenterol. 2017;112:740-751. Slide credit: clinicaloptions.com

Conclusions
 NAFLD is a complex disease trait with pathogenesis and progression
determined by combinations of genetic and environmental factors
 Principal drivers of NAFLD pathogenesis are metabolic stress due to calorific
excess with consequent development of obesity and insulin resistance
– These trigger a variety of hepatotoxic insults (oxidative stress, mitochondrial
dysfunction, and lipotoxicity) that lead to hepatocellular injury, inflammatory
activation, and ultimately, fibrogenesis
– Knowledge of the pathogenic mechanisms underpinning NAFLD has helped
identify promising therapeutic targets
 The highly variable natural history of NAFLD/NASH and substantial
interpatient variation in outcomes makes diagnosis and risk stratification
challenging; however, numerous tools are available to help
Slide credit: clinicaloptions.com
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