Emerging Epidemic of Nonalcoholic Fatty Liver Disease Kathleen E Corey, MD, MPH, MMSc Director, Mass General Fatty Liver Clinic
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