Emerging Epidemic of Nonalcoholic Fatty Liver Disease

Kathleen E Corey, MD, MPH, MMSc Director, Mass General Fatty Liver Clinic

Outline Global Prevalence of NAFLD

NAFLD Diagnostics

Treatment of NASH

Predictors of Outcome in NAFLD

What is NAFLD? • Chronic liver disease characterized by

excess storage of fat within the liver in the absence of significant alcohol use

• Type 2 Diabetes • Obesity • Dyslipidemia • Metabolic syndrome

• Obstructive sleep apnea

• Hypothyroidism • Polycystic ovary

syndrome

Major Comorbidities Emerging Associations

Steatosis Steatohepatitis

Cirrhosis

Nonalcoholic Fatty liver Disease

Fatty hepatocytes

Intracellular fat deposition

Steatosis

Fibrosis Inflammation, ballooning Fat deposits

Nonalcoholic Steatohepatitis (NASH)

Cirrhosis

Nodules surrounded by

fibrosis

NAFLD Global Prevalence: 25%

Z. Younossi et, Hep 2016

NASH Prevalence: 1.5-6.6%

NAFLD Prevalence Increases with Age

No difference in NAFLD prevalence by gender Slide Adapted and Courtesy of Z. Younossi Z. Younossi et, Hep 2016

Prevalence of NAFLD in High Risk Populations

Prevalence by Ultrasound from NHANES III

Slide Adapted and Courtesy of Z. Younossi Z. Younossi et, Hep 2016 Z. Younossi et al. Medicine 2012

NAFLD not confined to high-risk populations Prevalence in lean: 7% Women Young age Normal ALT

Screening for NAFLD: Area of Controversy

KE Corey et al. DDS 2016

Markov model comparing 2 management strategies for 50- year-olds with diabetes •No Screening strategy: no screening, although NASH may be incidentally dxd NASH Screening strategy: one-time screening ultrasound, + ultrasound → liver biopsy, + NASH → medical therapy (vitamin E) End-points 1) Life years, 2) QALYs gained, 3) costs, 4)incremental cost-effectiveness ratios (ICERs), 5) Progressive liver disease

Conclusion: No significant benefit to population based screening at this time

Screening for NAFLD: Area of Controversy

• European Association for the Study of the Liver Guidelines (2017) – NAFLD screening in individuals with:

• Insulin resistance/Diabetes • Metabolic syndrome • Obesity

• American Association for the Study of Liver Disease Guidelines (2012) – Screening not recommended

Testing for Incidentally Noted Steatosis

• Steatosis on imaging: – Evaluation warranted regardless of LFTs as

they are normal in 70-80% of NAFLD/NASH – Screen for metabolic syndrome (high risk for

NASH) – Screen for secondary causes of FLD including

alcohol, hepatitis C (gt 3), medications

Testing for Incidentally Noted Abnormal LFTs

• NAFLD is most common cause of abnormal LFTs in US

• Evaluate for all causes of abnormal LFTs

• Ultrasound evaluation for steatosis

Who Should Undergo Liver Biopsy?

• Patients with uncertain diagnosis – Ex. Steatosis on US but high titer ANA, ASMA

• Patients with evidence of chronic liver disease – Ex. Low platelets, evaluated INR

• Patients with high risk non-invasive scores – NAFLD Fibrosis Score (composite of

laboratory tests) – Elastrography

What Predicts Outcomes in NAFLD?

• 619 patients from US, Europe and Thailand with biopsy-proven NAFLD – 45.9% NASH/borderline NASH – 54.1% non-NAFLD

• Followed for median 12.6 years

• 33.2% died or underwent liver transplantation

P Angulo et al. Gastro 2016

All Fibrosis Stages Predict Death/Liver Transplant

P Angulo et al. Gastro 2016

Fibrosis Predicts Death and Liver Transplantation

Treatment should target those with fibrosis, diabetes, tobacco use. P Angulo et al. Gastro 2016

Weight Loss is Foundation of NASH and Fibrosis Treatment • Prospective cohort of 293 adults with

biopsy-proven NASH in Havana, Cuba • Placed on low-fat, average protein diet

with focus on complex carbohydrates, fruits, vegetables

• Counseled to decrease caloric intake

E. Vilar-Gomez et al. Gastro 2016

Weight Loss is Foundation of NASH and Fibrosis Treatment • Physical activity: started 90 minutes per

week, increase to 200 minutes per week

• Followed for 12 months

• Repeat biopsy at study completion

E. Vilar-Gomez et al. Gastro 2016

Weight Loss Varied Among Subjects

70%

12% 8% 10%

0% 10% 20% 30% 40% 50% 60% 70% 80%

<5% 5-6.99% 7-9.99% >=10%

Percent Total Body Weight Loss in Vilar-Gomez Study

Weight Loss Can Meaningfully Impact NASH

E. Vilar-Gomez et al. Gastro 2016

Weight Loss Can Meaningfully Impact NASH

Limitations • Only assessed impact of weight loss on

histology after12 months; no longer term follow-up of weight or histology

• Only 30% achieved >5% TBW

• Weight loss surgery is an effective alternative in appropriate patients

Standard of Care NASH Treatment: Lifestyle

Treatment Dose Population Outcomes Weight loss via lifestyle intervention

7-10% total body weight loss

NASH with and without DM

Improvement in steatosis and inflammation

Weight loss via Surgery

Overweight F3-4 BMI>29, all F stages

Improves NASH and fibrosis in majority, increase LY and QALY

Mediterranean Diet

Radiographic NAFLD

Improvement in radiographic NAFLD, controlled for weight loss

Exercise ≥90 minutes weekly

Radiographic NAFLD

Improvement in radiographic steatosis, ALT level

Ekstedt et al., J of Hepatology 2007 , Mummadi et al., CGH 2008 . Pomrat et al., Hepatology 2010 , Taitano et al,. J Gastro Surg 2015, Musso et al. Hepatology 2010, LB Van Wagner Ann Hep 2011, Ryan et al. J Hep 2013, Vilar-Gomez et al., Gastro 2016, Klebanoff et al. Hepatology 2017

Standard of Care NASH Treatment: Medications

Treatment Dose Population Outcomes Vitamin E 800 units daily NASH without DM Improvement in

steatosis and inflammation

Pioglitazone 30-45 mg daily NASH with DM Improvement in steatosis and inflammation

Ekstedt et al., J of Hep 2007

Mummadi et al., CGH 2008

Pomrat et al., Hep 2010

Taitano et al,. J Gastro Surg 2015 Musso et al. Hep 2010 LB Van Wagner Ann Hep 2011

Vitamin E for NASH: PIVENS Trial

A. Sanyal et al., NEJM 2010

Vitamin E for NASH: PIVENS Trial

A. Sanyal et al., NEJM 2010

Placebo VitE Pio Vit E vs Placebo

Pio vs. Placebo

Primary Outcome, %

19%

43%

34%

0.001

0.04

NASH resolution,%

21%

36%

47%

0.05

0.001

Fibrosis Improvement, %

31%

41%

44%

0.24

0.12

Vitamin E and NASH • Prostate CA: Avoid VitE in individuals with

personal or family history of prostate CA • Mortality: Discuss risk of all-cause mortality

with patients and weight risks and benefits • Use: Vitamin E recommended for use in biopsy-

proven NASH in non-diabetics

• Aim: Evaluate impact pio on NASH

• Intervention: Pio 45mg or placebo for 18 months; all received counseling on hypocaloric diet

• Population: 101 Adults with pre-DM or DM, with biopsy-proven NASH

K Cusi et al., Ann Int Med 2016

In Diabetes and Pre-DM, Pio Improved NASH

K Cusi et al., Ann Int Med 2016

Pio Leads to Weight Gain

K Cusi et al., Ann Int Med 2016

• Pio group gained significantly more weight than placebo (+2.5kg, 95% CI 0.4-4.5, P=0.02)

• Less than seen in pio group in PIVENS (mean 4.7 kg), maybe due to dietary counseling

• Pio had positive impact on lipids – HDL (44mg/dL vs 40mg/dL, P<0.001) – Triglycerides (127mg/dL vs 144mg/dL, P=0.018)

Pioglitazone and Adverse Effects

• CHF: For CHF, careful monitoring for CHF and rapid discontinued for symptoms recommended

• Bladder CA: Do not prescribe in those with bladder cancer and with caution in those with history of bladder cancer

• Weight gain: Requires dietary couseling • Use: Biopsy-proven NASH in those with

diabetes

RW Nesto et al., Circ 2003 AM Lincoff et al., JAMA 2007 JA Dormandy et al., Lancet 2005

Pharmacotherapy in Development Treatment MOA Population Outcomes Current Trial Ongoing Phase 3 Trials Genfit/Elafibranor (GFT-505), 120mg PO daily

Dual PPAR alph/delta activator

NAS≥3 Phase 2b GOLDEN-505 In NAS>4, resolution of NASH & in responders, reduction in fibrosis No benefit in NAS<4

RESOLVE-IT NASH and NAS>=4, F1-3 72 weeks PE: 1) NASH resolution w/o worsening fibrosis, 2) mortality, cirrhosis, LRO

OCA 25mg po daily

Farnesoid receptor X ligand/agonist

Non-cirrhotic NASH, 50% DM

Phase 2 FLINT: NAS improvement in 46% vs. 21% placebo, Fibrosis≥1 35% vs.19%

REGENERATE NASH and fibrosis 72 weeks PE: 1) Fibrosis improvement, no worsening NASH, 2) NASH resolution

Ongoing Phase 2 Trials

Conatus/Emricasan

Pan-caspase inhibitor, oral High first pass metabolism

Different etiologies of cirrhosis including 23% NASH

Reduction in caspase-cleaved CK18 Improvement in MELD, TB, INR, in those with MELD>15

ENCORE-NF trial 72W NASH + fibrosis (no cirrhosis) PE: reduction in fibrosis

Galectin/GR-MD-02 Galectin-3 protein binds to terminal galactose residues on glycoproteins, inhibits galectin in macrophages

NASH with fibrosis Decreased markers of fibrosis

NASH-CX trial NASH cirrhosis PE: HVPG NASH-FX Trial NASH + AF PE: MRE

Pharmacotherapy in Development Treatment MOA Population Outcomes Current Trial Ongoing Phase 2 Continued

Cenicriviroc oral

Immunomodulator blocks 2 chemokine receptors, CCR2, CCR5 on monocytes, lymphocytes, HSC, Kupffer cells; developed as HIV drug

HIV Improved APRI and FIB-4 ORION 24 weeks in suspected NAFLD, IR, obesoty PE: Imaging, IS, LFTs CENTAUR 2 year NASH + fibrosis (no cirrhosis) PE: histology

Galmed/Aramchol

Conjugate of cholic acid and arachidic acid, first-in-class member of synthetic Fatty-Acid / Bile-Acid Conjugates (FABACs)

NASH Reduced liver fat in dose dependent manner 100mg 2.89%, 300mg 12.57%, improved HOMA

Victoza/Liraglutide GLP-1 analog, improves IS, FAO, hepatic glucose metabolis; decrease lipogenesis

NASH and DM

NASH resolution: LGT 39% vs. placebo 9%

Simtuzumab (LOXL-2 inhibitor)

inhibitory monoclonal antibody against L2 type of lysyl oxidase (LOX), enzyme family that stabilizes ECM

NASH Improved ALT and AST NASH cirrhosis PE: HVPG, liver-related events/mortality NASH+ Advanced fibrosis PE: Hepatic collagen

Pharmacotherapy in Development Treatment MOA Population Outcomes Current Trial Ongoing Phase 2 Continued

GS-4997 Inhibits Apoptosis signal-regulating kinase 1 (ASK1): MAP3 kinase, activates p38/JNK pathway, causes apoptosis and fibrosis Contributes to IR

Murine models Decreases diet-induced steatosis and fibrosis

Open label, 24 week study GS-4997 +/- simtuzumab in NASH with F2-3

Amlexanox IkB kinase inhibitor Animal models Decreases steatosis, hepatic inflammatory gene expression

12 weeks in DM, fatty liver on imaging PE: Hepatic fat, A1C, weight

PXS-4728A Selective irreversible VAP-1 inhibitor VAP1 supports liver recruitment of lymps, ROS generation

Murine model (STZ/HFD) Improved NASH histology Phase 1 recently completed

IMM-124E IgG rich extract of bovine colostrum from cows immunized against LPS

10 patients, bx-proven NASH

30 days improved IS and glycemia

Phase 2 evaluating impact on MR fat in progress

Solithromycin Macrolide antibiotic Murine model Decreased ballooning and inflammation

Phase 2 open label for 13 weeks rx on non-cirrhotic NASH PE: Histology

Conclusions • NAFLD has a 25% prevalence globally • Fibrosis most important predictor death/LTx • Weight loss is the foundation of therapy • For biopsy-proven NASH with Fibrosis

– Vitamin E 800U daily without diabetes – Pioglitazone 30-45mg with diabetes – Consider weight loss surgery

• Discuss adverse events

Thank you