1. Non Alcoholic Fatty Liver Disease NAFLD
Summary of current knowledge
NAFLD
January 2018

2. Natural History of Nonalcoholic Fatty Liver Disease (NAFLD)
RISK FACTORS
Overweight
Obesity
Metabolic syndrome
Dyslipidemia
Type 2 diabetes
Polycystic ovary syndrome ?
HCC ?
> 1-2%/year
25%
NAFLD
NASH F0 F1 F2 F3 F4
Regression
25%, with progression of
one stage fibrosis per decade ?
Isolated liver steatosis
Decompensation
NAFLD
Adapted from Diehl AM. NEJM 2017;377:

3. NAFLD: progression of disease
Healthy Liver
NAFLD
NASH
Cirrhosis
Reversible
Reversible
Irreversible
Large droplets
of fat
Bloated
hepatocyte
Collagen
fibers
Scarring
Hepatocyte
Nucleus
Inflamed
dying
hepatocyte
Remnant of
dead cells
Small droplets
of fat
Displaced
nucleus

4. Liver histology in NAFLD
NASH
Cirrhosis
Hepatic steatosis
≥ 5%
Current or previous
Lobular and portal inflammation
Yes
Hepatocellular injury (ballooning) No
Fibrosis
F0 to F3 F4
Histology scoring
NAS (NAFLD Activity Score), reflects disease activity: unweighted composite of
Steatosis (0 to 3)
Lobular inflammation (0 to 3)
Ballooning (0 to 2)
SAF Score: semi-quantitative score of
Activity (lobular inflammation + ballooning) = NAS (0 to 8)
Fibrosis (0 to 4)
NAFLD
Adapted from Chalasani N. Practice Guidance from the AASLD;Hepatology 2018;67:

5. Liver-related symptoms or signs ? Abnormal liver biochemistries ?
Screening for NAFLD
Incidentally discovered Hepatic Steatosis (Imaging)
Liver-related symptoms or signs ? or
Abnormal liver biochemistries ?
YES NO
Evaluation for potential NAFLD
Assess for metabolic risk factors
Obesity
Diabetes
Dyslipidemia
Alternate causes
Significant alcoholism (> 21 standard drinks/week in men, > 14 in women)
Medications
Type 2 diabetes
Exclude other etiologies for steatosis, chronic liver diseases
NAFLD Fibrosis Score (NFS)
FIB-4 index
Elastography
NAFLD
Adapted from Chalasani N. Practice Guidance from the AASLD; Hepatology 2018;67:

6. Non-invasive Scores of NAFLD
NAFLD Fibrosis Score (NFS) *
FIB-4 **
Age +
AST
ALT
Platelet count
BMI
Albumin
Impaired fasting glucose or diabetes
* NFS: or gihep.com/calculators/hepatology/nafld-fibrosis-score
** FIB-4: or
gihep.com/calculators/hepatology/fibrosis-4-score
NAFLD

7. Assessment of NAFLD Non invasive evaluation
Presence of metabolic syndrome: predictive of steatosis LIVER BIOPSY
NFS*, FIB-4, vibration controlled transient elastography, magnetic resonance elastography: predictive of advanced fibrosis  LIVER BIOPSY
Serum ferritin and iron saturation: if , marker of possible hepatic injury and/or hemochromatosis (homozygote or heterozygote C282Y HFE mutation)  LIVER BIOPSY
High serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (> 5 ULN aminotransferases, high globulins, or high total protein to albumin ratio)  work-up for autoimmune liver disease
Consider presence of commonly associated comorbidities (central obesity, hypertension, dyslipidemia, diabetes or insulin resistance, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea)
* NFS is based on 6 variables (age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio) and is calculated using the published formula
NAFLD
Adapted from Chalasani N. Practice Guidance from the AASLD ; Hepatology 2018;67:

8. Likelihood of NASH and fibrosis in patients with NAFLD
Low
Intermediate
High
Age
< 40
> 40
> 50
Type 2 diabetes No
Yes, well-controlled
Yes
Obesity
Hypertension
Fibroscan kPa
< 7
> 7
> 8.5
AST
< 20
> 20
and
AST/ALT ratio ≥ 1
NFS (NAFLD Fibrosis Score)
< -
> 0.676
FIB-4
< 1.3
> 2.67
Patients at risk for clinical progression
Steatosis ≥ 1
Ballooning ≥ 1
Inflammation ≥ 1
NAS (NAFLD Activity Score) ≥ 4
≥ F2
NAFLD
Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

9. Comorbidities of NAFLD
CV diseases
Metabolic comorbidities
More frequent
More severe
Cancer
Liver complications
Cirrhosis
End-stage liver disease
Liver (HCC)*
GI malignancies
Colon (men)**
Esophagus
Stomach
Pancreas
Non-GI malignancies
Kidney (men)
Breast (women)**
HR of * 17 ; ** 2 ; *** 1.9
Adapted from Kim GE. J Hepatol 2018;68:140-6 ;
Chalasani N. Practice Guidance from the AASLD; Hepatology 2018;67:
NAFLD

10. Management of patients with NASH and fibrosis
Interventions recommended
Objective/restrictions
Benefit
Weight loss (Hypocaloric Diet
[ by 500-1,000 kcal/day])
3-5%
7-10%
 > 10%
Improve steatosis
Improve NASH, including fibrosis
NASH resolution and  fibrosis
Moderate-intensity exercise
(30 min/day x 3-5 times/week)
If isolated
Prevent or reduce steatosis
Limit alcohol consumption (≤ 2 drinks/day men, ≥ 1 drink women)
All patients
Coffee consumption (≥ 2 cups/day)
 Inflammation and fibrosis
Modification of CVD risk factors
CV morbidity and mortality
Statins
If dyslipidemia
Interventions to consider
Pioglitazone
In patients with or without type 2 diabetes
Improves liver histology
Vitamin E (rrr a-tocopherol)
In non-diabetic patients
Foregut bariatric surgery
In otherwise eligible obese
Omega-3 fatty acids
If hypertriglyceridemia
Improve hypertriglyceridemia
Not recommended : Metformin, GLP-1 agonists (liraglutide), Systematic bariatric surgery, Ursodeoxycholid acid
Adapted from Chalasani N. Practice Guidance from the AASLD ; Hepatology 2018;67: ;
Diehl AM. NEJM 2017;377:
NAFLD

11. Endpoints in clinical trials of NAFLD and NASH
Outcomes
Hard endpoints
Surrogate endpoints
Clinical
All cause mortality
Liver-related mortality
Child-Pugh and MELD scores
Hepatic venous portal gradient
Hepatic decompensation
Progression to cirrhosis
Fibroscan (kPa) and magnetic resonance elastography
Biomarkers (pro-C3, FIB-4, NFS, enhanced liver fibrosis)
Metabolic
 in hepatic fat content
MRI-derived proton density fraction, Multiparametric MRI, Controlled attenuation parameter
 in insulin resistance
HbA1c, fasting glucose, HOMA-IR
Impact on lipids
 in weight/BMI
Inflammatory
 in necro-inflammation
Multiparametric MRI, Liver enzymes
 in hepatocyte ballooning
Fibrosis
 in fibrosis stage
NAFLD
Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

12. NASH-new serum non-invasive biomarkers
Not yet fully validated
Could diagnose NASH and its severity
Could identify patients likely to respond to therapy
Chitinase-3-like protein 1(CHI3L1) – YKL-40
Enhanced Liver Fibrosis (ELF) Test
Comprised of TIMP-1 (tissue inhibitor of matrix metalloproteinase-1), PIII-NP (mino-terminal peptide of type III procollagen), and hyaluronic acid
Pro C3
Derived from synthesis of type III collagen
FIB-C3 Score
HepQuant STAT
Quantitative liver function test 60 min after oral administration of 4 mg tetra-deuterated cholic acid
Non-invasive score-4 (NIS4)
Detect patients with NAS ≥ 4 and F ≥ 2
Comprised of Chitinase-3-like protein 1(CHI3L1), alpha2-macroglobulin, microRNA 34a (MIR34a), and HbA1C
NAFLD
Adapted from Harrison SA. AASLD 2017

13. Current Status of Pharmacologic Treatments for NASH
No approved therapies for NASH
Currently available therapeutics with (some) proven efficacy
Vitamin E
Pioglitazone
NAFLD

14. NASH: targets for therapeutics
Insulin resistance
Cell stress apoptosis
Inflammation
Fibrogenic remodeling
Insulin resistance modifiers
Cell stress modifiers
Anti-inflammatory agents
Anti-fibrotic agents
Exemples of drugs in development
PPAR
FXR agonist (obeticholic acid, GS-9674)
GLP-1
FABAC
FGF-21 (BMS )
Thyroxine analog
Vitamin E
ASK-1 inhibitor (selonsertib)
PPAR-γ agonsit
FXR agonist
Dual PPAR-/δ agonist
FGF-21
FGF-19-like agent
CCR2-CCR5 antagonist
ASK-1 inhibitor
Galectin 3
Lysyl oxidase-like 2 inhibitor
Endpoints for clinical trials
Disease Activity (steatohepatitis) = NAFLD Activity Score (NAS)
Disease Progression = Fibrosis Stage
Clinical outocmes: Cirrhosis (MELD, Portal hypertension), Liver-related outcome, death
NAFLD
Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print) ; Diehl AM. NEJM 2017;377:

15. NASH – Pharmacological agents in development
Drug
Class
Mechanism of action
Objective
Phase 2b
Aramchol
Synthetic fatty acid/bile acid conjugate
Impacts lipogenesis by upregulates the ABCA1 reverse cholesterol transporter and functions
 liver fat and NAFLD activity score without  of fibrosis
Emricasan
Pan-caspase inhibitor
Blockage of apoptotic and inflammatory caspase activation involved in hepatocyte cell death
 fibrosis and portal hypertension
GR-MD-02
Galectin-3 protein inhibitor
Anti-fibrogenesis
Phase 3
Obeticholic acid
Semi-synthetic derivative of acid chenodeoxycholic
acid
Agonist of the farnesoid X receptor : downregulates hepatic glucose and lipid metabolism.
May also  portal pressure and have anti-inflammatory and antifibrotic activity
 fibrosis without  NASH ;
NASH resolution without  of fibrosis
Elafibranor
Dual PPAR-a/d agonist
Regulation of metabolic homeostasis, inflammation, cellular growth, and differentiation
NASH resolution without  of fibrosis ;
Clinical outcomes
Cenicriviroc
dual CCR2/CCR5 antagonist
Reduction of hepatic inflammation and fibrosis
 NAFLD activity score without  of fibrosis ;
 fibrosis without  NASH
Selonsertib (GS-4997)
Apoptosis signal regulating kinase 1 (ASK1) inhibitor
Reduction in oxidative stress-related cell death, fibrosis and inflammation
NAFLD
Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

16. Improvement of NASH with pharmacologic agents
Results of trials for individual treatment agents *
Vitamin E
Placebo
Pioglitazone
Obeticholic acid
Elafibranor
Cenicriviroc
Selonsertib
Simtuzumab 20 40 60 80
100
Improvement in hepatic steatosis
p = 0.005
p < 0.001
p = 0.10
p = 0.001 54 31 69 61 38 35 18 72 70
102 98 39
Resolution of NASH
p = 0.05
p = 0.01
p = 0.08 36 21 47 22 13 29 5
Improvement in fibrosis
p = 0.24
p = 0.12
p = 0.02
p = 0.004 41 44 19 10
145
144 57 37
p = ns %
* Enrollment criteria and durations of therapy differed between studies, and the primary endpoint definitions were not identical
NAFLD
Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

17. Combination of metabolic damages
NASH
Combination of metabolic damages
to the liver
Prevention
and Lifestyle
Modifications
are key !
NAFLD