1

Zobair Younossi MD, MPH, FACG, AGAF, FAASLD

Chairman, Department of Medicine, Inova Fairfax Hospital

Vice President for Research, Inova Health System

Professor of Medicine, VCU-Inova Campus

Affiliate Professor of Biomedical Sciences,

George Mason University

Falls Church, Virginia

Hepatology Update: The Year in ReviewFatty Liver Disease

The Spectrum of NAFLD

Normal

NA

FL

D S

pec

tru

m

• NASH requires specific pathologic criteria• Exclusion of liver diseases• Important for prognosis

AASLD Guideline:• NAFLD: 6-33%• NASH: 3-5%

• Obese: 75% NAFLD and 19% NASH• Morbidly Obese:

•NAFLD: 93% •NASH: 26-49%

• Diabetes: 49.5-87%

4.7% to 38.5%

23.4%

9.3% to 29%

17.1%

12.9-28.9%

30-46%

15.8%

Epidemiology

Ludwig 1980 , Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Younossi 1997, Matteoni/Younossi 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong/Younossi 2001, Bugianesi 2002, Ratziu 2002, Saddeh/Younossi 2002, Harrisson 2003, Marchesini 2003, Younossi 2004, Gramlich/Younossi 2004, Fassio 2004, Sanyal 2004, Ong/Younossi 2005, Adams 2005, Ong/Younossi 2008, Mishra/Younossi 2008, Rafiq/Younossi 2010, Hossain/Younossi 2009, Kim/Younossi 2010, Stepanova/Younossi 2010, Hossain/Younossi 2010, Stepnaova, Younossi 2012, Younossi 2012, Chalasani, Younossi 2012

Hilden 77, Ground 82, Hultcrantz 86, Nomura 88, Nonomura 92, El-Hassan 92, Propst 95, Lonardo 97, Bellentani 2000, Clark 2001, Ruhl 2004, Browning 2004, Angelico 2005, Hamagushi 2005, Jimba 2005, Lin 2005, Fan 2005, Zelber 2006, Zhou 2007, Fan 2007, Targher 2007, Lazo 2008, Younossi 2011, Chalasani 2012

• Prevalence of pediatric NAFLD is 2.6-17.3%• Autopsy study from UCSD (N=742)

• Prevalence: 9.6%, rates increasing with age• More common in boys• Highest rate in Hispanics Schwimmer JB 2006, Argo C 2009

• 11,613 NHANES-III participants

• NAFLD was defined as fat by ultrasound, absence of excessive alcohol use and other chronic liver diseases• Prevalence of NAFLD in

obese and overweight: 17.7% (N=2,061)

• Prevalence of NAFLD in lean individuals (BMI<25): 3.7% (N=431)

• 11,613 NHANES-III participants

• NAFLD was defined as fat by ultrasound, absence of excessive alcohol use and other chronic liver diseases• Prevalence of NAFLD in

obese and overweight: 17.7% (N=2,061)

• Prevalence of NAFLD in lean individuals (BMI<25): 3.7% (N=431)

Although Most Cases are in Obese/Overweight, Lean Individuals Can Also Have NAFLD

Younossi Z et al. Medicine 2012

Lean NAFLD(N=431)

Overweight/Obese NAFLD

(N=2061)

p

White, % 72.48 ± 4.51 76.33 ± 2.58 0.2992

AA, % 10.25 ± 2.08 8.10 ± 1.26 0.1132

Hispanic, % 6.97 ± 1.64 7.74 ± 1.39 0.4621

Other ethnicity, % 10.30 ± 3.10 7.82 ± 1.71 0.4258

Male, % 43.57 ± 4.03 54.78 ± 1.70 0.0189

IR, % 13.35 ± 2.41 63.52 ± 1.77 <0.001

Diabetes, % 6.72 ± 1.41 16.13 ± 1.06 <0.001

High chol,% 62.65 ± 3.80 87.19 ± 1.53 <0.001

Hypertension, % 17.83 ± 2.39 39.10 ± 1.91 <0.001

Age, yrs 41.94 ± 1.15 49.10 ± 0.61 <0.001

Body Mass Index 22.17 ± 0.16 32.37 ± 0.24 <0.001

HOMA 2.77 ± 0.33 5.84 ± 0.30 <0.001

ALT: SI (U/L) 17.96 ± 0.98 25.63 ± 0.80 <0.001

AST: SI (U/L) 21.50 ± 0.60 24.82 ± 0.53 0.0002

What is new in 2015 regarding the clinical impact of NAFLD?

What is new in 2015 regarding the clinical impact of NAFLD?

Hepatology Update: The Year in Review

Fatty Liver Disease

2

NAFLD in Clinical Practice

••

• Houston VA patients (2001–2011) with elevated ALT and no liver diseases (n = 19,692)

• Random sample (n = 450)• Structured chart review to

confirm the criteria for NAFLD and metabolic syndrome (n=358)

• Houston VA patients (2001–2011) with elevated ALT and no liver diseases (n = 19,692)

• Random sample (n = 450)• Structured chart review to

confirm the criteria for NAFLD and metabolic syndrome (n=358)

NAFLD Case Definition (n = 251)

NAFLD Case Definition (n = 251)

Persistently increased ALT

No viral hepatitis

No excessive alcohol (2 yr prior)

Metabolic syndrome, BMI ≥30

Blais P, et al. Am J Gastroenterol. 2015;110:10-14.

- Recognition of ALT increase- Diagnosis of NAFLD/NASH- Recommend lifestyle changes- Referal specialist evaluation

NAFLD Care defined as:39% 22% 15% 10%

Only the magnitude and proportion of ALT elevation predictive of receiving NAFLD care

61%

No NAFLD Care

In 2015, Despite Being A Common Cause of CLD, NAFLD Remains Under-recognized in the Clinical Practice

Natural History of NAFLDNatural History of NAFLD

Hepatology Update: The Year in Review

Fatty Liver Disease

Which Type of NAFLD Progresses?

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 2004, Sanyal 2004, Ong 2005, Adams 2005, Ong 2006, Rafiq 2008, Stepanova 2010, Younossi 2012

Hossain N, et al Gastro and Hepatology 2009

NAFLD with liver biopsy (N=432)

In multivariate analysis, elevated AST and ALT, presence of diabetes mellitus, male gender and Caucasian ethnicity were associated withmoderate to severe fibrosis (p<0.0001)

Factors Advanced FibrosisOR (95% CI)

P‐value

Hypertension 1.61 (1.21‐2.01) 0.0374Diabetes 1.64 (1.13‐2.17) 0.0258HTN and DM 1.69 (1.11‐2.28) 0.0246

HTN+DM+VO 1.72 (1.13‐2.31) 0.0205

What Are the Clinical Predictors of Advanced Fibrosis In NAFLD?

3

Histologic NAFLD (N=289)

Clinico-demographic data from the time of biopsy• NASH (59.2%), non-NASH (40.8%)

• NASH patients were predominantly female, had higher AST, ALT and higher fasting serum glucose

Mortality: During median follow-up of 150 months• NASH patients had higher risk of

liver-related mortality than non-NASH NAFLD (p-value = 0.0026).

Histologic NAFLD (N=289)

Clinico-demographic data from the time of biopsy• NASH (59.2%), non-NASH (40.8%)

• NASH patients were predominantly female, had higher AST, ALT and higher fasting serum glucose

Mortality: During median follow-up of 150 months• NASH patients had higher risk of

liver-related mortality than non-NASH NAFLD (p-value = 0.0026).

Stepanova M, et al. Dig Dis Sci 2013

What Are the Clinical Predictors of Mortality In NAFLD?

Risk factorOverall mortality

aHR(95% CI)

Liver-related mortalityaHR

(95% CI)

NASH 1.13 (0.74 - 1.71) 9.16 (2.10 - 9.88)

Age 1.07 (1.05 - 1.10) 1.06 (1.02 - 1.10)

Male gender 0.95 (0.62 - 1.47) 1.44 (0.62 - 3.34)

Caucasian race 1.67 (0.92 - 3.06) 1.85 (0.62 - 5.47)

Obesity 0.91 (0.60 - 1.40) 0.88 (0.38 - 2.04)

Type II diabetes 2.09 (1.39 - 3.14) 2.19 (1.00 - 4.81)

Hyperlipidemia 1.01 (0.68 - 1.52) 0.48 (0.19 - 1.23)

Stepanova M, et al. Dig Dis Sci 2013

What Are the Clinical Predictors of Mortality In NAFLD?

NAFLD liver biopsy and mortality data (N=209)

Biopsies were read centrally

During follow-up (146 months), 31% of patients died with 9% dying of LRM

Despite the pathologic protocol, NASH had higher LRM than non-NASH NAFLD• 13.0% vs. 1.3%, p = 0.0047

NAFLD liver biopsy and mortality data (N=209)

Biopsies were read centrally

During follow-up (146 months), 31% of patients died with 9% dying of LRM

Despite the pathologic protocol, NASH had higher LRM than non-NASH NAFLD• 13.0% vs. 1.3%, p = 0.0047

Portal inflam (grade≥2) [6.68 (2.20-20.3), p<0.001]

Ballooning (grade≥2) [5.32 (1.89-14.9), p=0.001]

MD bodies (grade≥2) [4.21 (1.66-10.7), p=0.002]

Portal fib (grade>2) [14.1 (5.47-36.5), p<0.001]

Pericellular fib (grade>2) [4.86 (1.73-13.7), p=0.003]

Portal inflam (grade≥2) [6.68 (2.20-20.3), p<0.001]

Ballooning (grade≥2) [5.32 (1.89-14.9), p=0.001]

MD bodies (grade≥2) [4.21 (1.66-10.7), p=0.002]

Portal fib (grade>2) [14.1 (5.47-36.5), p<0.001]

Pericellular fib (grade>2) [4.86 (1.73-13.7), p=0.003]

Younossi Z et al Hepatology 2011

Univariate survival analyses [HR (95% CI) , p-value]

On multivariate analysis, only significant fibrosis (grade > 2) was an independent predictor of LRM

What Are the Histologic Predictors of Mortality In NAFLD?

What is new in 2015 about progressiveness of NAFLD?

What is new in 2015 about progressiveness of NAFLD?

Hepatology Update: The Year in Review

Fatty Liver Disease

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Prognostic Relevance of Liver Histology in Nonalcoholic Fatty Liver Disease:

The PRELHIN study

International study of NAFLD (N=619) diagnosed between 1975-2005

All liver biopsies centrally ready

Median follow-up 12.6 yrs

193 who died or had OLT• 74 (38.3%) of CV disease

• 36 (18.7%) of non-liver CA

• 18 (9.3%) of liver complication

International study of NAFLD (N=619) diagnosed between 1975-2005

All liver biopsies centrally ready

Median follow-up 12.6 yrs

193 who died or had OLT• 74 (38.3%) of CV disease

• 36 (18.7%) of non-liver CA

• 18 (9.3%) of liver complication

Angulo P et al AASLD 2014

FibrosisStage

Hazard Ratio (95% CI) P value

01234

1 (ref)2.4 (0.63, 8.91)7.5 (2.26, 24.94)13.8 (4.35, 43.65)

47.5 (11.94, 188.61)

0.2 0.01

< 0.001< 0.001

Multivariate Analysis

In 2015, we know that NASH (especially with DM) is associated with LRM and stage of fibrosis>2 is predictive of LRM

NAFLD and HCCNAFLD and HCC

Hepatology Update: The Year in Review

Fatty Liver Disease

Several case reports and case series of well documented HCC in patients with NAFLD/NASH

Two population-based cohort studies of NAFLD• One study suggested 0.3% over 6 years

Three clinic based cohort studies of NAFLD or NASH (not restricted to cirrhosis)• Up to 6% absolute risk of HCC in approximately 20

year follow up

• Lower relative risk compared to alcohol or HCV

Several case reports and case series of well documented HCC in patients with NAFLD/NASH

Two population-based cohort studies of NAFLD• One study suggested 0.3% over 6 years

Three clinic based cohort studies of NAFLD or NASH (not restricted to cirrhosis)• Up to 6% absolute risk of HCC in approximately 20

year follow up

• Lower relative risk compared to alcohol or HCV

NAFLD and HCC

White D, Kanwal F, El-Serag H. Clin Gastro Hepatol 2012

What is new in 2015 regarding association of NAFLD with HCC?

What is new in 2015 regarding association of NAFLD with HCC?

Hepatology Update: The Year in Review

Fatty Liver Disease

5

Cases of HCC in the United States: Data from surveillance, epidemiology and end results (SEER)-medicare registries (2004–2009)

SEER represents 28% of U.S. population: Cohort included 5,748 cases of HCC and 17,244 non-HCC matched controls (3:1) Number of HCC cases increased between 2004-2009

Cases of HCC in the United States: Data from surveillance, epidemiology and end results (SEER)-medicare registries (2004–2009)

SEER represents 28% of U.S. population: Cohort included 5,748 cases of HCC and 17,244 non-HCC matched controls (3:1) Number of HCC cases increased between 2004-2009

Cause of chronic liver disease in HCC

NAFLD and HCC

Younossi Z, et al. EASL 2015, Vienna. #O041Younossi Z, et al. EASL 2015, Vienna. #O041

OR (95% CI)

Male 4.62 (4.17, 5.11)

Non‐white, non‐black race(Asians and Hispanics)

1.74 (1.54, 1.97)

Presence of any liver diseases

HCV 69.29 (60.30, 79.62)

HBV  47.34 (36.73, 61.01)

NAFLD 13.64 (12.16, 15.29)

Lower Charlson Comorbidity Index: Healthier scores

0.17 (0.15, 0.19)

Independent factors associated with HCC

Fewer HCV/HBV pts died within 1-year of dx vs NAFLD (50% vs 62%, p<0.05) Fewer HCV/HBV pts died within 1-year of dx vs NAFLD (50% vs 62%, p<0.05)

Adjusted survival curve by liver disease

HR (95% CI)

Older age 1.02 (1.01, 1.02)

Lower income 1.33 (1.20, 1.48)

Un‐staged tumor 1.24 (1.12, 1.37)

Medicare eligibility, disabled/ESRD 1.39 (1.22, 1.58)

NAFLD 1.21 (1.01, 1.45)

Factors independently associated with one-year mortality (HCC cohort)

HR (95% CI)

Liver transplant recipients 0.13 (0.09, 0.17)

Having localized tumor stage 0.51 (0.47, 0.55)

Factors protective against 1-year mortality

*Adjusted for age at HCC diagnosis & tumour stage

HCVHBVNAFLD

0 2

0.4

4 6 8 10 1212-month of follow-up after HCC diagnosis

0.5

0.6

0.7

0.8

0.9

1.0

Co

x p

rop

ort

ion

al h

aza

rd m

od

el

NAFLD and HCC

Younossi Z, et al. EASL 2015, Vienna. #O041

In 2015, we are increasingly recognizing that NAFLD is an important cause of HCC with higher mortality

Clinical and Routine Labs- Not very Helpful

New Modalities - Fibroscan: Central Obesity

- MR Elastography betterClinical Predictive Panels - Based on routine tests Fibrosis: - APRI, Fib-4, Simple, BARD, BAAT, Fibrotest, NAFLD Fibrosis Score

NASH:- Hair, NASH test, NPI

Liver Biopsy &

Pathologic Protocols

New Pathogenic Biomarkers

Fibrosis:Fibrotest, ELF, Fibrometer

NASH:CK-18, NAFLD Diagnostic Panel

Routine Radiologic Test(US, CT, MRI)

- Only able to detect fat- Not Fibrosis or NASH

Diagnostic & PrognosticBiomarkers for NASH What is new in 2015 about non-invasive tests

for NAFLD?What is new in 2015 about non-invasive tests

for NAFLD?

Hepatology Update: The Year in Review

Fatty Liver Disease

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Magnetic Resonance Elastography vs. Clinical Prediction Models for Advanced Fibrosis in NAFLD

Cross-sectional analysis of 102 patients with biopsy-proven NAFLD

Cui JY, et al. EASL 2015, Vienna. #O020Cui JY, et al. EASL 2015, Vienna. #O020

Fibrosis stage 0 1 2 3 4 Total

Number of patients 48 26 9 13 6 102

= Advanced fibrosis: 19/102 (18.6%)

Primary analysis: ROC curves of 8 CPRs

CPR AUROC 95% CI

1) FIB‐4 0.861 (0.775–0.946)

2) Lok Index 0.838 (0.731–0.944)

3) Bonacini Cirrhosis 

Discriminant Score0.826 (0.725–0.926)

4) AST to ALT Ratio 0.825 (0.732–0.918)

5) NAFLD Fibrosis Score 0.818 (0.704–0.932)

6) BARD 0.816 (0.723–0.910)

7) APRI 0.807 (0.702–0.911)

8) NASH CRN Model 0.796 (0.678–0.915)

CPRs ranking by AUROC

AST to ALT ratioAPRIBARDFIB-4NAFLD Fibrosis ScoreBonacini CDSLok IndexNASH CRN Model

FIB-4

p-value: AUROC of 2D-MRE vs FIB-4 DeLong Test

Primary outcome: 2D-MRE vs FIB-4 ROC curve of 2D-MRE

2D-MRE FIB-4

0.9

1.0

0.8

0.7

AU

RO

C

p=0.039

In 2015, FIB-4 or NFS can be used to determine candidates for MRE to avoid a liver biopsy for detection of advanced fibrosis

AUROC: 0.957

p<0.001

Cui JY, et al. EASL 2015, Vienna. #O020

Magnetic Resonance Elastography vs. Clinical Prediction Models for Advanced Fibrosis in NAFLD

InsulinResistance(Adipose, liver and muscle)

Gut MicrobiomAnd Increased

EndotoxinLevel

Pro-inflammatory Adipocytokines

(Lept, Resistin, IL-6, TNF-α)

Anti-inflammatoryAdipocytokines(Adiponectin)

Oxidative Stress

FIBROSIS

NASH

Apoptotic Pathway

Lipoxicity

2nd hit

Modified from Mishra P, Rafiq N, Younossi Z. Practical Management of Liver Disease 2008

Obesity

ER Stress

Hepatic Steatosis

Free Fatty Acids

Peroxisomal Fatty Acid OxidationLipid Peroxidation

Impaired Mitochondrial

Function

2nd hit

1st hit

No ProgressionProgression

Genes That Influence these Pathways and the Environment

Mazzella N et al. CLD 2014

Targets Used for Treatment of Non-alcoholic Fatty Liver Disease

7

Treatment of NAFLD: Weight Loss Pharmacologic Treatment of NAFLDMetabolic Treatment Target: Insulin Resistance

Study N Drug Duration(months)

Design ALT Histology

Marchesini 14 Metformin 4 Open label + N/A

Nair 15 Metformin 12 Open label + N/A

Bugianesi 55 Metformin 6 RCT + +

Uygun 17 Metformin 6 RCT + -

Duseja 7 Metformin 6 Open label + N/A

Schwimmer 10 Metformin 6 Open label + N/A

Morita 5 Nateglinide 5 Open Yes Yes

Pharmacologic Treatment of NAFLDMetabolic Treatment Target: Insulin Resistance

Author N Drug Time DM? Cirrh-osis ALT Fat Bal Infl Fibrosis

Caldwell 2001

10 Troglit400 mg

3-6 months 1/10 Yes Yes ? No ?Yes No

Promrat2004

18 Pio30 mg

12 No No Yes Yes Yes Yes Yes

Aithal2008 74 Pio

30 mg 12 mo No Yes Yes Yes Yes Yes Yes

Belfort 2006 55 Pio

45 mg 6 mo Yes No Yes Yes Yes Yes ---

Ratziu2008 63 Rosi

8 mg 12 mo Yes No Yes Yes --- --- ---

Sanyal 2010

247

Pio 30 mg 96 wk No No Yes� �Yes --- Yes� ---

Mahady 2011* n/a n/a n/a n/a Yes

PIVENS: RCT NASH without DM (N=247)• Pioglitazone 30 mg/d (N=80) for 96 weeks

• Vit E 800 IU/d (N=84) for 96 weeks

• Placebo (N=83) for 96 weeks

• Pre- and Post Liver Biopsy

• Primary endpoint: NAS score decrease of 2 (no higher fib)

• Secondary endpoints (Path features, enzymes, etc.)

Met primary endpoint: Pi 34%, VE 43% & P 19%

Histologic secondary endpoints were seen for both Pio and Vit E but no improvement in fibrosis scores

Conclusions: - Vit E superior to placebo

- Pio did not meet pre-specified primary endpoint

- Other issues include weight gain during treatment and that improvement of liver enzymes not sustained

PIVENS: RCT NASH without DM (N=247)• Pioglitazone 30 mg/d (N=80) for 96 weeks

• Vit E 800 IU/d (N=84) for 96 weeks

• Placebo (N=83) for 96 weeks

• Pre- and Post Liver Biopsy

• Primary endpoint: NAS score decrease of 2 (no higher fib)

• Secondary endpoints (Path features, enzymes, etc.)

Met primary endpoint: Pi 34%, VE 43% & P 19%

Histologic secondary endpoints were seen for both Pio and Vit E but no improvement in fibrosis scores

Conclusions: - Vit E superior to placebo

- Pio did not meet pre-specified primary endpoint

- Other issues include weight gain during treatment and that improvement of liver enzymes not sustained

Sanyal A et al N Engl J Med. 362(18), 1675-85 (2010)

Metabolic Treatment Target: Insulin Resistance

Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH. (Strength – 1, Evidence - A)

Pioglitazone can be (?) used to treat steatohepatitis in patients with biopsy-proven NASH. However, it should be noted that majority of the patients who participated in clinical trials that investigated pioglitazone for NASH were non-diabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established. (Strength – 1, Evidence- B)

8

Pharmacologic Treatment of NAFLDTreatment Target: Oxidative Stress

AuthorsN Dose Comparators Outcomes

Arendt 80 1000 IU/d PlaceboImproved steatosis (assessed

by CT scan) vs placebo

Sanyal 247 800 IU/dPioglitazone,

placebo

Improved steatosis, inflammation, and ballooning vs

placebo

Lavine 173 800 IU/dMetformin,

placeboImproved steatohepatitis and

ballooning vs placebo

Harrison 45 1000 IU/d Placebo Improved fibrosis vs baseline

Sanyal 20 400 IU/dVitamin E + pioglitazone

Improved steatosis vs baseline

Dufour 48 800 IU/dUDCA + placebo, placebo

Improved steatosis, inflammation, and ballooning vs

baseline

Vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population. (Strength -1, Quality - B)

Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis (Strength - 1, Quality - C)

Treatment: Lipid Lowering Agents

Study Design (mts) Meds N ALT Hist

Laurin Open label (12) Clofibrate 16 - -Fernández- Open label (12) Fenofibrate 16 + +/-Miranda CBasaranoglu RCT (1) Gemfibrozil 46 + NAHorlander Open label (12) Atrovastatin 7 + +Kiyici Open label (6) Atrovastatin 27 + NAHatzitolios Open label (6) Atrovastatin + NAGomez- Open label (12) Atrovastatin 25 + NADominguezRallidis Open label (7) Pravastatin 5 + +/-Ekstedt Retrospect (10.3-16.3 yrs) Statins 68 + +Merat RCT (6) Probucol 30 + NANelson RCT (12) Simvastatin 14 + -Park Open label (24) Ezetimibe 45 + +/-

Study Design (mts) Meds N ALT Hist

Laurin Open label (12) Clofibrate 16 - -Fernández- Open label (12) Fenofibrate 16 + +/-Miranda CBasaranoglu RCT (1) Gemfibrozil 46 + NAHorlander Open label (12) Atrovastatin 7 + +Kiyici Open label (6) Atrovastatin 27 + NAHatzitolios Open label (6) Atrovastatin + NAGomez- Open label (12) Atrovastatin 25 + NADominguezRallidis Open label (7) Pravastatin 5 + +/-Ekstedt Retrospect (10.3-16.3 yrs) Statins 68 + +Merat RCT (6) Probucol 30 + NANelson RCT (12) Simvastatin 14 + -Park Open label (24) Ezetimibe 45 + +/-

Given the lack of evidence to show that patients with NAFLD and NASH are at increased risk for serious drug-induced liver injury from statins, statins can be used to treat dyslipidemia in patients with NAFLD and NASH(Strength – 1, Quality – B)

Until RCTs with histological endpoints prove their efficacy, statins should not be used to specifically treat NASH (Strength – 1, Quality B)

Antioxidants• Betaine• N-Acetyl-cysteine• Lecithin• Silymarin• Beta-carotene

Anti-TNF agents (Pentoxifylline) Probiotics (VSL#3) ACE inhibitors/ARBs Caspase inhibitors Cytoprotective agents/Bile Acids

- Ursodeoxycholic acid (UDCA)

Antioxidants• Betaine• N-Acetyl-cysteine• Lecithin• Silymarin• Beta-carotene

Anti-TNF agents (Pentoxifylline) Probiotics (VSL#3) ACE inhibitors/ARBs Caspase inhibitors Cytoprotective agents/Bile Acids

- Ursodeoxycholic acid (UDCA)

Other Treatment Regimens for NAFLD with Limited Data

What is new in 2015 about treatment of NAFLD?

What is new in 2015 about treatment of NAFLD?

Hepatology Update: The Year in Review

Fatty Liver Disease

9

New Targets For Treatment of NASH

Class Drug

Farnesoid X receptor (FXR) agonist Obeticholic acid

Anti-lysyl oxidase-like 2 monoclonal antibody

Simtuzumab

Fatty acid/bile acid conjugate Aramchol

Dual inhibitor of CCR2 and CCR5 Cenicriviroc

Dual peroxisome proliferator-activated receptor alpha/delta agonist

GFT505

Obeticholic Acid (OCA)

• Semisynthetic bile acid analog (6α-ethyl-chenodeoxycholic acid) 100 times more potent than chenodeoxycholic acid in binding farnesoid X receptor

• Treatment with OCA has been associated with

• Improved insulin sensitivity

• Reductions in markers of liver inflammation and fibrosis

• Reductions in triglyceride levels

• Dose-related weight loss

• OCA was generally well tolerated; adverse effects were similar across treatment groups

• Increases in LDL and reductions in HDL

• Semisynthetic bile acid analog (6α-ethyl-chenodeoxycholic acid) 100 times more potent than chenodeoxycholic acid in binding farnesoid X receptor

• Treatment with OCA has been associated with

• Improved insulin sensitivity

• Reductions in markers of liver inflammation and fibrosis

• Reductions in triglyceride levels

• Dose-related weight loss

• OCA was generally well tolerated; adverse effects were similar across treatment groups

• Increases in LDL and reductions in HDL

Mudaliar S, et al. Gastroenterology. 2013;145:574‐582

FLINT Phase 2 Trial DesignThe Farnesoid X Receptor Ligand Obeticholic Acid (OCA) in NASH Treatment

N=283Patients w/

Histological Evidenceof NASH

Placebo QD

Screening (Biopsy)

Follow up

OCA 25 mg QD Follow up

72 week Treatment Period 24 week off-drug

Primary endpoint: Histological improvement defined as:• No worsening in fibrosis; and• Decrease in NAS of ≥ 2 points

Interim Analysis when 50% of patients completed treatment and

had an end-of-treatment liver biopsy

Brent A Neuschwander-Tetri et al Lancet 2014

FLINT Study: Improved Liver Histology after 72 Weeks of Treatment

Brent A Neuschwander-Tetri et al Lancet 2014

Subgroup with T2DM (OCA: 53% vs placebo 19%, p<0.05)• Modest improvement in IR• Lipid changes in OCA vs. placebo (HDL ↓, LDL↑)Decision:• Stop treatment phase of trial – as it met efficacy endpoint and no further biopsies • Planned phase III RCT

Subgroup with T2DM (OCA: 53% vs placebo 19%, p<0.05)• Modest improvement in IR• Lipid changes in OCA vs. placebo (HDL ↓, LDL↑)Decision:• Stop treatment phase of trial – as it met efficacy endpoint and no further biopsies • Planned phase III RCT

10

Secondary Histologic Endpoints

Endpoint OCA 25 mg Placebo P-value

Fibrosis Improvement (%) 35% 19% 0.01

Hepatocellular Ballooning (%) 46% 31% 0.03

Steatosis (%) 61% 38% 0.001

Lobular Inflammation (%) 53% 35% 0.007

NASH Resolution (%) 22% 13% 0.08

Neuschwander-Tetri et al. Lancet 2014

Lipid Parameters MeasuredTotal cholesterol LDL HDL Triglycerides

OCA Pla OCA Pla OCA Pla OCA Pla

Baseline 190 197 112 111 42 44 196 178

∆ Baseline -72 wks (n=257)

+6* -7* +9* -8* -1* +1* -20 -7

∆ Baseline -96 wks (n=240)

-12 -8 -12 -12 +1 +1 -3 0

* P 0<0.01 for OCA vs. placebo

Neuschwander-Tetri et al. Lancet 2014

Changes in Lipid Profile

FLINT: Safety and Tolerability

• Pruritus higher in OCA group (23% vs 6%) and of higher grade (predominantly moderate pruritus)

• 1 discontinuation of OCA due to pruritus

• Other AEs were similar to placebo

• No differences in severe AEs and most events judged to be unrelated to therapy

• Pruritus higher in OCA group (23% vs 6%) and of higher grade (predominantly moderate pruritus)

• 1 discontinuation of OCA due to pruritus

• Other AEs were similar to placebo

• No differences in severe AEs and most events judged to be unrelated to therapy

Neuschwander-Tetri et al. Lancet 2014 A large Phase III double-blind, placebo-controlled trial to assess

the safety and efficacy of OCA in adult patients with NASH

Aramchol—Mechanism of Action

Synthetic molecule: Conjugated bile acid + saturated fatty acid1

Reduces hepatic fat via 2 pathways:• Inhibits stearoyl coenzyme A desaturase 1 (SCD1)

activity, a key enzyme of fatty acid metabolism1,2

• Activates cholesterol efflux by stimulating ATP-binding cassette transporter A1 (ABCA1), a pan-cellular cholesterol pump1,3

Synthetic molecule: Conjugated bile acid + saturated fatty acid1

Reduces hepatic fat via 2 pathways:• Inhibits stearoyl coenzyme A desaturase 1 (SCD1)

activity, a key enzyme of fatty acid metabolism1,2

• Activates cholesterol efflux by stimulating ATP-binding cassette transporter A1 (ABCA1), a pan-cellular cholesterol pump1,3

1. Safadi R, et al. Clin Gastroenterol Hepatol. 2014;12:2085-2091. 2. Leikin-Frenkel A, et al. Arch Med Res. 2010;41:397-404. 3. Goldiner I, et al. Biochem J. 2006;396:529-536.

11

Aramchol—3-Month Phase IIa Trial Liver Fat Content Change from Baseline

Placebo (n = 19)

Aramchol 100 mg (n = 18)

Aramchol 300 mg (n = 20)

Safadi R, et al. Clin Gastroenterol Hepatol. 2014;12:2085-2091.

P =.02 for aramchol 300 mg vs placebo

Frequency of adverse effects were similar between groups; all adverse effects were mild/moderate

Phase IIb, 1-year, multicentre, randomised, double-blind, placebo-controlled, international trial to assess the safety and efficacy of 2

aramchol doses (400 mg or 600 mg) vs placebo in noncirrhotic adult patients with NASH

GFT505—Mechanism of Action

• Dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist1

• Improves lipid and glucose metabolism in prediabetics2

• Improves hepatic and peripheral insulin sensitivity in obese patients3

• Improves steatohepatitis and fibrosis in mouse models1

• Antifibrotic and anti-inflammatory effect1

• Dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist1

• Improves lipid and glucose metabolism in prediabetics2

• Improves hepatic and peripheral insulin sensitivity in obese patients3

• Improves steatohepatitis and fibrosis in mouse models1

• Antifibrotic and anti-inflammatory effect1

PPAR-α PPAR-δExpression Hepatocytes Ubiquitous

Action Lipid and lipoprotein metabolismAnti-inflammatory

Mitochondrial function, fatty acid oxidation & ISAnti-inflammatory

1. Staels B, et al. Hepatology. 2013;58:1941-1952. 2. Cariou B, et al. Diabetes Care. 2011;34:2008-2014. 3. Cariou B, et al. Diabetes Care. 2013;36:2923-2930.

Phase IIb, 1-year, international, multicentre, randomised, double-blind, placebo-controlled trial to assess the safety and efficacy of GFT505 (80 mg or 120 mg vs. placebo in noncirrhotic adult patients with NASH

Simtuzumab—Mechanism of Action

• Humanised monoclonal antibody1

• Inhibits cross-linking of collagen in pathologic stroma1,2

• Lysyl oxidase-like 2 (LOXL2) levels may correlate with extent of fibrosis and clinically relevant endpoints for idiopathic pulmonary fibrosis (IPF)2

• Very limited data from early human trials

• Humanised monoclonal antibody1

• Inhibits cross-linking of collagen in pathologic stroma1,2

• Lysyl oxidase-like 2 (LOXL2) levels may correlate with extent of fibrosis and clinically relevant endpoints for idiopathic pulmonary fibrosis (IPF)2

• Very limited data from early human trials

1. Ratziu V. Nat Rev Gastroenterol Hepatol. 2013;10;646-685. 2. Barry-Hamilton V, et al. Nat Med. 2010;16:1009-1017.

Phase IIb, 240-week dose-ranging (200 mg or 700 mg IV q2 weeks, randomised, double-blind trial to assess the efficacy and safety of

simtuzumab in adult cirrhotic patients with NASH; followed by optional open-label phase

• Since the original description of NASH over 30 years ago, despite dozens of clinical trials of different agents, we have failed to identify a single effective treatment for most patients with NASH

• Research design flaws and Little attention to the complex pathogenic

• There some promising new treatment protocols

• Given the heterogeneity of NASH phenotype, targeted treatment using a personalized medicine approach based on pathogenic pathways, clinical and prognostic biomarkers may be required

• Since the original description of NASH over 30 years ago, despite dozens of clinical trials of different agents, we have failed to identify a single effective treatment for most patients with NASH

• Research design flaws and Little attention to the complex pathogenic

• There some promising new treatment protocols

• Given the heterogeneity of NASH phenotype, targeted treatment using a personalized medicine approach based on pathogenic pathways, clinical and prognostic biomarkers may be required

NASH Treatment Summary2015

Younossi Z et al APT 2013

12

Elevated aminotransferasesFatty Liver by imaging

•Exclude other causes of CLD•Confirm lack of excessive ETOH•Assess risk factors•Consider Assessment for IR

• Suspicion for other CLD• Dx of NAFLD uncertain

• No evidence of other CLD• Young age• No evidence of adv LD

• Self directed life style modifications• Professionally directed life style modification• Repeat lab in 6 months

• Goals achieved• Monitor q 6-12 m

• Unsuccessful• Risks (DM, IR)• Liver enzymes elevated• High NAFLD Fibrosis score

Liver biopsy

How Do We Manage our NAFLD Patients in 2015?

Simple Steatosis Histologic NASH

• Continue life style and modifications

• If non-diabetic: VIT E• If diabetic: Pioglitazone?

• Medical treatment unsuccessful

• Consider RCT of new agents• Consider Bariatric surgery

for those who meet criteria

Refer to primary for management of MS

and risk of CVD

Liver biopsy

How Do We Manage our NAFLD Patients in 2015?

NAFLD is common but is under-recognized in clinical practice NASH patients have higher LRM Stage 2 or greater in NASH is predictive of LRM Liver biopsy remains the gold standard for diagnosis of NASH MRE is the most promising non-invasive test for NASH Clinical predictive tests for fibrosis (NFS and Fib-4) and MRE

may be useful clinically to avoid liver biopsy Current treatment considerations for patients with NASH:

• Life style modifications for all• Vitamin E for non-DM NASH • ??Pio for DM with NASH but be aware of safety concerns• Consider bariatric surgery for morbidly obese+/-DM with NASH

Future treatment considerations:• Clinical trials of new agents are underway

NAFLD is common but is under-recognized in clinical practice NASH patients have higher LRM Stage 2 or greater in NASH is predictive of LRM Liver biopsy remains the gold standard for diagnosis of NASH MRE is the most promising non-invasive test for NASH Clinical predictive tests for fibrosis (NFS and Fib-4) and MRE

may be useful clinically to avoid liver biopsy Current treatment considerations for patients with NASH:

• Life style modifications for all• Vitamin E for non-DM NASH • ??Pio for DM with NASH but be aware of safety concerns• Consider bariatric surgery for morbidly obese+/-DM with NASH

Future treatment considerations:• Clinical trials of new agents are underway

Hepatology Update: The Year in ReviewFatty Liver Disease (Summary for 2015)