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Non-Alcoholic Fatty Liver Disease (NAFLD):
Emerging Concepts
Victor Ankoma-Sey, MD, FACP, FAASLD
Director, Liver Associates of Texas, P.A.
Director, Liver Transplantation Program,
Sherri & Alan Conover Center for Liver Diseases & Transplantation, J.R.
Walter, Jr Transplant Institute, Houston Methodist Hospital, Houston
Clinical Associate Professor of Medicine, Baylor College of Medicine
Non Alcoholic Fatty Liver Disease (NAFLD) Emerging Concepts: Outline
Definition
Epidemiology
Natural History & Prognosis
Pathogenesis
Evaluation & Management
Approach to NAFLD in Ghana
Summary
NAFLD
Definition
NAFLD- Definition
NAFLD- Nonalcoholic Fatty Liver Disease
Hepatic Steatosis by Imaging OR Histology
WITHOUT other etiology for hepatic fat accumulation
There is no significant alcohol consumption
there are no competing etiologies for hepatic steatosis
there are no co-existing causes for chronic liver disease
Fatty Liver: Etiologies
Cleveland E et al Clinical Liver Disease, April 2018
NAFLD Risk Factors: Established Association -
Metabolic Syndrome (Syndrome X)
ATP III Criteria > 3 of the following
• Diagnosed based 3 or more of the following features
- Abdominal obesity ( waist > 40”/ 102 cm for
men and >34.5”/ 88 cm for women)
- Triglyceride level > 150 mg/dL
- HDL < 40 mg/dL for men and < 50 mg/dL for
women
- Fasting blood sugar ≥ 110 mg/dL/Type 2 DM:
insulin resistance (IR)
- Blood pressure ≥ 130/85 mm of Hg
NAFLD~ The Hepatic Manifestation of the Metabolic Syndrome
NAFLD Risk Factors: Emerging Associations
Polycystic ovary syndrome
Hypothyroidism
Obstructive sleep apnea
Hypopituitarism
Hypogonadism
Pancreatic-duodenal resection
NAFLD
Epidemiology
Loomba and Sanyal Nature Rev
Gastro 2013
Global Correlation of Obesity & NAFLD
Global Prevalence of NAFLD
Younossi, ZM, Clinical Liver Disease April 2018
Fructose & Sucrose intake & Obesity & NAFLD Prevalence Rates
Jensen, Thomas et al J of Hepatology 2018
Added Sugar Consumption = refined beet, sugar cane sucrose & high-fructose corn syrup (HFCS). Currently 15% of overall energy intake in the ave. western diet – higher % in younger individuals & ethnic minorities
( African American, Hispanic, Native American & Pacific Islanders)
Fructose : O.J. will kill you !
High-Fructose Corn Syrup (HFCS = mixture of fructose & glucose monosaccharides; usual ratio 65:35)
Table sugar/sucrose (disaccharide of fructose & glucose)
Sweeteners in soft drinks eg O.J.
Unique hepatic metabolism of fructose : leads to hepatic and extra hepatic fat accumulation - a potent risk factor for NAFLD
Fructose intake predicts development of NAFLD & MetS/Obesity
A unique aspect of fructose metabolism :transient depletion in intracellular phosphate & ATP: transient block in protein synthesis; induction of oxidative stress & uric acid production; Insulin Resistance & mitochondrial dysfunction NAFLD .cf glucose. Mediated by Fructokinase C pathway in the liver.
Prevalence of NASH & Advanced Fibrosis in type 2 DM
Lonardo A et al J of Hepatology 2018
NAFLD
Natural History
Genetics
– PNPLA3 gene (Others include NCAN, GCKR, LYPLAL1)
Other (HCV/HIV)
Men,
NAFLD - Prognosis • Increased overall mortality compared to matched control populations.
• Commonest cause of death in patients with NAFLD, NAFL and NASH is
cardiovascular disease.
• Increased liver-related mortality rate – increasingly common indication for
liver transplantation (15-20%).
Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC.
American Journal of Gastroenterology doi:10.1038/ajg.2011.327
NAFLD
Genes & Natural History
Nature Genetics 40, 1461 - 1465 (2008)
PNPLA3
Genetic Susceptibility to NASH
African American Caucasian Hispanic
%
NAFLD G-allele frequency
Santoro et al., Hepatology. Oct 2010; 52(4): 1281–1290.
PNPLA3 G-Allele Frequency Accounts for Ethnic Variation in NASH
More NAFLD Risk Genes
NAFLD
Pathogenesis
Innate immunity
2
Lipotoxicity 1
1
1
1
1
1
Endotoxin
Cholesterol tox
Hypoxia
Adipokines
Tetri, Hepatology 2010
High glycemic diet; high fat diet & high salt diet & PNPLA3 gene polymorphism all exacerbate fructose-induced NAFLD. Fructose from sucrose & HFCS (High-fructose corn syrup) : O.J…
NAFLD
Evaluation of NAFLD
Evaluation of Suspected Fatty Liver
Diagnosis requires:
- Hepatic Steatosis by imaging or histology :
Evaluation of a Patient with NAFLD Goal: to determine if advanced fibrosis/NASH is present ?
Non-invasive assessment of steatohepatitis and advanced fibrosis in NAFLD
Clinical
Blood/serologic Biomarkers
Imaging
Clinical Assessment for possible NASH Fibrosis
Assessment of Advanced Fibrosis in NASH: Serum Biomarkers & Scoring Systems
Hassan, K et al WJG 2014
NAFLD fibrosis score
• < -1.455: predictor of absence of
significant fibrosis (F0-F2 fibrosis)
• ≤ -1.455 to ≤ 0.675: indeterminate score
• > 0.675: predictor of presence of
significant fibrosis (F3-F4 fibrosis)
NAFLD Fibrosis Score
– Three values: No advanced fibrosis, Indeterminate, Advanced fibrosis
• Good test for determining patients without advanced fibrosis ((NPV 88%)
Imaging Modalities in NAFLD: Assessment of Fibrosis
Transient elastography
Adapted from Cleveland E et al Clinical Liver Disease, April 2018
• FibroScan (Transient Elastography)
• Fast, painless, noninvasive, reproducible for advanced fibrosis
• Increase sample size than liver biopsy
• XL probe to try and diminish results in obese patients
• 88% Sen and 95% Spec
• 78-84% will have reliable liver stiffness measurement
• Can not determine NASH
FibroScan – Assessment of Fibrosis in NAFLD
Liver Stiffness Correlates with Fibrosis Stage
0 1 2 3 4
Normal Chronic Liver Disease
<
0.0001*
<
0.0001*
<
0.0001*
Kruskal Wallis
Dunnett’s Test
α = 0.05
0
2
4
6
8
10
12
14
Liv
er
Sti
ffn
ess (
kP
a)
(Fibrosis Stage) Yin et al. CGH 2007;5:1207-13
MR Elastography (MRE) of the Liver
Plastic Tube
Passive Driver
-90
0
+90
Am
pli
tud
e (
mm
)
-70
0
+70
Am
pli
tud
e (
mm
)
Active
Driver
G
rad
ien
t-E
ch
o M
RE
Phase
Difference
θ
MRE Correlates with Fibrosis Stage and NASH
Stage 0 1 2 3 4
1.7kPa 2.1 3.2 6.2 6.9
Loomba et al., Hepatology 60:1919–1927, 2014
N=117 with NAFLD
AUC = 0.924
P<0.001
• MR Elastography:
Provides standard MR evaluation
Fat quantification
Fibrosis measurement
“whole liver” evaluation
Sen 85% Spec 93%
Composite Clinical Assessment for Advanced Fibrosis in NAFLD
Konerman,MA et al J of Hepatology 2018
NAFLD Assessment of Fibrosis : What to do... in clinical practice ?
Vilar-Gomez & Chalasani N J of Hepatology 2018
NAFLD
Management
Management of Patients with NAFLD
Dyson JK et al. Frontline Gastroenterology 2014
54
Weight
loss
-Options:
-Diet - Exercise
- Surgery - Pharmacotherapy
• 1) Lifestyle changes – WEIGHT LOSS
– Explain diagnosis and set realistic target weight
– Nutritional counselling – refer to dietician
– Exercise – 3-4 times per week, expend 400 kcal per session
– Promrat et al 2010: Intensive lifestyle intervention (diet, exercise,
behaviour modification) vs structured education alone.
• Weight loss 9.3% vs 0.2% (p = 0.003)
• Decrease in NAS 72% vs 30% (p=0.03)
Younossi ZM (2008). Review article: current management of NAFLD and NASH. Alimentary Pharmacology and Therapeutics 28:
2-12
Dowman JK, Armstrong MJ, Tomlinsomn JW, Newsome PN (2011). Current therapeutic strategies in NAFLD. Diabetes, Obesity
and Metabolism 13: 692-702
Management of NAFLD in Primary
Care
Diet
Drugs
Exercise
Nutritional Treatment Options in NAFLD
Manuel Romero-Gómez, Shira Zelber-Sagi, & Michael Trenell J of Hepatology 2017
Coffee: Protective Effect in NAFLD
Manuel Romero-Gómez, Shira Zelber-Sagi, & Michael Trenell J of Hepatology 2017
Coffee: Protective Effect in NASH, T2DM & Liver Cancer
Diet
Drugs
Exercise
Exercise & NAFLD
Manuel Romero-Gómez, Shira Zelber-Sagi, & Michael Trenell J of Hepatology 2017
NAFLD
Diet
Drugs
Exercise
Targeting Components of Metabolic Syndrome in NAFLD Patients with T2DM
Dyson JK et al. Frontline Gastroenterology 2014
Targeting Components of Metabolic Syndrome in NAFLD Patients with HTN and Hyperlipidemia
Dyson JK et al. Frontline Gastroenterology 2014
Obesity Reduction Drugs for Obese NAFLD Patients
Potential Drug Targets in NAFLD
Konerman MA et al J of Hepatology 2018
Treatment Paradigm
notes
Cenicriviroc
CCR2/CCR5 inh FDA fast tracked
Emricacsan,
Caspase
inhibitor
• Decreases CK18
and ALT in HCV
Liraglutide,
GLP-agonist
Approved
for T2DM
• 170 pt IIb study
underway Cysteamine,
antioxidant
IIa/b
IIa
IIa
IIa
Phase Treatment Regimens
• 100mg once daily PO, >550 pts studied to date,
CCR2/5 involved in macrophage recruitment,
maturation and in stellate cell activation
• Up to 500mg daily PO, Conatus
• Also studied in HCV and graft preservation
• 70mg once a day S/C for 24 months
6/27 pts “decreased” NAS score
• 300, 375, or 450 mg once daily PO
41% decr in AST, ns impr in adip, CK18
NVD in Huntington’s Chorea trial
Pipeline for NASH – 2018
• oral ASK1 inhibitor IIa • Inhibits inflammatory and ROS pathways
Treatment Paradigm
notes
FXR agonists.
OCA, INT777, PX-
102, WAY-362
• Endpoints met
• Elev alk phos,
lipids and itching
GFT-505
PPAR a/d
agonist
• Benefits at 60mg
and 30mg
Aramchol,
FA/bile acid
conjugate
• FDA fast tracked
for 240 pt study
• Subcut admin Simtuzumab
LOXL2 mAb
Pipeline for NASH - 2018
IIb/III
IIb
IIa/b
IIb
Phase Treatment Regimens
• 25mg once daily PO, for INT 747 (OCA)
• 40-100mg daily PO, Genfit Pharma
• Also studied in dyslipidemia, (effective) and
T2DM
• 300mg once a day for 3 months
• Effective in ph 2a in decr easing liver fat
by 12%, also decr ALT and incr adiponectin
• Multiple doses in development,
cross link inhibitor
• FDA fast tracked IIb • Binds to galectin 1 and 3,
• 26 IV infusion doses
Galectin GR-MD-02
Earliest launch dates Q4 2018 ?
Managing Complications of NASH Cirrhosis
Routine medical management of Portal HTN complications: Ascites/SBP; variceal bleed; Hepatic encephalopathy Liver Transplantation evaluation for decompensated cirrhosis/MELD > 15
Dyson JK et al. Frontline Gastroenterology 2014
Approach to NAFLD in Ghana
Increase awareness of NAFLD – community, MDs, local government partners
Prevention and Rx of Metabolic Syndrome: Obesity and Diabetic Clinics- lifestyle modification a key component
Early detection of NAFLD with appropriate risk assessment and prompt referral via non–invasive techniques: safe, low cost and reliable.
Fatty Liver Referral Clinic : a multidisciplinary approach -hepatologists, diabetologists, radiologists, dieticians, psychologists, physical therapists/exercise physiotherapists -nurses
Agyei-Nkansah, Adwoa . Ghana Med J 2017;51 (3): 98-100
NAFLD- Summary
NAFLD has tremendous clinical, economic burden to patients and to society and this burden is growing globally
NASH is the progressive form of NAFLD
Pathogenesis is complex & biomarkers based on pathogenetic pathways are evolving
Histologic advanced fibrosis stage predicts liver related mortality- Noninvasive assessment is promising & facilitates screening
Comprehensive lifestyle intervention with a calorie-restricted diet, exercise and behavior therapy: cornerstone of NAFLD Mx
There are currently no FDA-approved Rx. Pharmacologic Rx currently targeted to control DM or hyperlipidemia
Prevention –is crucial especially in developing countries