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