Updates in Nonalcoholic Fatty Liver Disease (NAFLD) Danielle - - PowerPoint PPT Presentation

Danielle Brandman, MD, MAS Program Director, Transplant Hepatology Fellowship Director, UCSF Fatty liver clinic Associate Professor of Medicine

Updates in Nonalcoholic Fatty Liver Disease (NAFLD)

Disclosures

• Allergan, Gilead, NGM, Grifols: Research funding, clinical trials

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

NAFLD: worldwide epidemic

Younossi, Nat Rev Gastroenterol Hepatol, 2017.

Epidemiology

• Prevalence of NAFLD: ~30% US population
• Prevalence of NASH: 3-5% US population

Farrell, Hepatology, 2006. Younoussi, Hepatology, 2015.

Epidemiology

• Prevalence of NAFLD: ~30% US population
• Prevalence of NASH: 3-5% US population

Farrell, Hepatology, 2006. Younoussi, Hepatology, 2015.

NAFLD NAFL

Steatosis without inflammation

NASH

Steatosis + inflammation

NASH + fibrosis

Cirrhosis HCC

NAFLD: Non-Alcoholic Fatty Liver

Spectrum of disease

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

Case

• 54yo woman with MetS with mild, dull RUQ pain x several months
• PMH: PreDM, dyslipidemia, HTN
• Meds: atorvastatin, lisinopril
• SocHx: Glass of champagne on special occasions
• FamHx: Parents with diabetes
• Labs: AST 38, ALT 71, albumin 4.1, INR 1.0, platelets 200
• Upon review of prior lab results, she has largely had AST 20s-40s

and ALT 40s-80s since 2015

What further work-up is needed?

A.

Liver biopsy

B.

Counsel her on lifestyle modification to try to lose weight and repeat liver tests again in 6 months

C.

Evaluate for other causes of chronic liver disease

D.

Transient elastography (Fibroscan)

What further work-up is needed?

A.

Liver biopsy

B.

Counsel her on lifestyle modification to try to lose weight and repeat liver tests again in 6 months

C.

Evaluate for other causes of chronic liver disease

D.

Transient elastography (Fibroscan)

Evaluation of Suspected NAFLD

• Liver tests
• Abdominal ultrasound
• Other serologic evaluation:
• HBsAg, sAb, cAb
• HCV Ab
• [AMA, IgM (for PBC if alkaline phosphatase elevated)]
• ASMA, ANA, IgG
• A1AT phenotype
• Iron, Tsat, ferritin
• Ceruloplasmin age < 45 or neuropsychiatric symptoms
• HAV Ab (for vaccination status)

NAFLD Diagnostic Criteria

• Diagnostic criteria
• Hepatic steatosis on imaging or liver biopsy
• No “significant” alcohol intake
• Absence of other causes of liver disease
• No medications known to cause hepatic steatosis

NAFLD Diagnostic Criteria

• Diagnostic criteria
• Hepatic steatosis on imaging or liver biopsy
• No “significant” alcohol intake
• Absence of other causes of liver disease
• No medications known to cause hepatic steatosis

NAFLD is a diagnosis of exclusion

NAFLD

A Clinically Silent Disease

• Symptoms:

– None: 20 - 77% – Right upper quadrant pain: 25 - 48% – Fatigue: 50 - 75% (Obstructive sleep apnea in 40%)

• Signs:

– Overweight/Obese: 85 - 95% – Acanthosis nigricans: 10 -15% – Hepatomegaly: 25 - 50%

• Laboratory:

– ALT, AST - modest elevation – “Normal enzymes” – Normal ALT <19-25 for women, <30-35 for men

Fibrosis progression

Fibrosis progression is different in NASH vs NAFL

NASH 7 years per 1 stage ~28 years 0 cirrhosis

Fibrosis progression is different in NASH vs NAFL

NASH 7 years per 1 stage ~28 years 0 cirrhosis NAFL 14 years per 1 stage ~56 years 0 cirrhosis

What is the best way to classify patients with NAFLD?

A.

Liver biopsy

B.

Fibroscan (transient elastography)

C.

MR elastography

D.

FIB-4

What is the best way to classify patients with NAFLD?

A.

Liver biopsy

B.

Fibroscan (transient elastography)

C.

MR elastography

D.

FIB-4

Liver biopsy

The liver biopsy is alive and kicking

Liver biopsy

Indications for Liver Biopsy

• Suspicious for NASH
• Significant liver enzyme elevation
• Diabetes
• Suspicious for advanced fibrosis or

cirrhosis

• Thrombocytopenia
• Imaging (e.g., splenomegaly)
• Noninvasive assessment: FIB-4, Fibroscan
• Diabetes
• Older age
• Unable to rule out other diseases

Chalassani, Hepatology 2017. Chalassani, Hepatology 2012.

NASH Advanced fibrosis

Noninvasive assessment of liver fibrosis

NAFLD fibrosis score=

• 1.675 + 0.037*age + 0.094*BMI +

1.13*IFG/DM + 0.99*AST:ALT – 0.13*platelets – 0.66*albumin

Noninvasive staging of NAFLD

AUROC Any fibrosis ≥F2 F3-4 Cirrhosis Transient elastography 0.74-0.78 0.79-0.84 0.83-0.88 0.86-0.93 MR elastography 0.83 0.91 0.89 0.97 NAFLD fibrosis score 0.82 0.72-0.82 0.73-0.86 0.77-0.92 FIB-4 0.8 0.72-0.83 0.78-0.86 0.78-0.88

Siddiqui, . . .Brandman et al. Clin Gastro Hep, 2018. Boursier, J Hepatol 2016. Imajo, Gastroenterology 2016. Hsu, Clin Gastro Hep, 2018.

Serial use of NFS/FIB-4 and TE

Petta, AP&T, 2017.

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

Prognosis of NAFLD by fibrosis stage

Steatosis NASH ± F1−F2 fibrosis HCC Death/ LTx Cirrhosis Advanced F3 fibrosis 12−40% 5−10% 0−50% 8% 13% 25−50% 14% 25% 7%

Day, J Hep, 2008.

What is the strongest predictor of outcomes in patients with NAFLD?

A.

Steatosis (fat) severity

B.

Liver size

C.

Fibrosis stage

D.

Number of ballooned hepatocytes on liver biopsy

What is the strongest predictor of outcomes in patients with NAFLD?

A.

Steatosis (fat) severity

B.

Liver size

C.

Fibrosis stage

D.

Number of ballooned hepatocytes on liver biopsy

Fibrosis is the most important predictor of death and liver-related events

Hagstrom, J Hep, 2017.

Overall mortality Liver-related event

Outcomes in NAFLD with F3-4 fibrosis

Decompensation CV events Non-HCC malignancy HCC

Vilar-Gomez, Gastro, 2018.

Increased risk of incident CV in NAFLD

Hagstrom, J Hep, 2018.

NAFLD is a risk factor for CVD

Targher, J Hepatol, 2016.

Fatal CVD Events OR 1.31 (95% CI 0.87-1.97) Fatal+non-fatal CVD Events OR 1.63 (95% CI 1.06-2.48) Non-fatal CVD Events OR 2.52 (95% CI 1.52-4.18)

NAFLD is a risk factor for CVD

NAFLD + elevated GGT or advanced fibrosis

Targher, J Hepatol, 2016.

Fatal CVD Events OR 3.28 (95% CI 2.26-4.77) Fatal+non-fatal CVD Events OR 1.94 (95% CI 1.17-3.21)

Younossi, Hepatology, 2015.

Association of NAFLD and HCC

HCC in non-cirrhotic patients

• Risk of having HCC in

absence of cirrhosis

 NAFLD: OR 5.4 (3.4-8.5)  MetS: OR 5.0 (3.1-7.8)

Mittal, Clin Gastro Hep, 2015.

2

NASH is a leading indication for LT

Noureddin, AJG, 2018.

LT for NASH-HCC is expected to rise more steeply than NASH alone

Shingina, Transplantation, 2019.

HCC No HCC

LT for NASH-HCC is expected to rise more steeply than NASH alone

Shingina, Transplantation, 2019.

HCC No HCC NASH HCV Female 36% 21% Age 62 57 NASH HCV Female 51% 30% Age 58 52

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

What treatment options are currently available to treat NAFLD?

A.

Bariatric surgery

B.

Vitamin E

C.

Ursodiol

D.

Lifestyle modification for weight loss

E.

B & D

What treatment options are currently available to treat NAFLD?

A.

Bariatric surgery

B.

Vitamin E

C.

Ursodiol

D.

Lifestyle modification for weight loss

E.

B & D

NAFLD treatment: Weight Loss

• Diet & Exercise

 Combination is best  Avoid fructose-sweetened beverages,

added sugars

 Exercise alone reduces liver fat

• Aerobic >150-250 minutes per week
• Resistance training 45 minutes/day x 3

days/week

• Harrison. Hepatology, 2009.

Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015 Chalasani , Hepatology 2012 .

Oh, Hepatology, 2015.

21 44 68

* ** **

*p<0.05, **p<0.01

Moderate or vigorous exercise reduces visceral adiposity

Aerobic vs resistance training

Lee, Diabetes, 2012..

Aerobic exercise

• 60 minutes
• 3 times per week
• 60-75% peak VO2

by week 2 Resistance exercise

• 60 minutes
• 3 times per week
• 10 whole body

exercises

• 1st 4 weeks: 1-2

sets 8-12 reps

• 2nd 4 weeks: 2

sets 8-12 reps

Barriers to exercise Associated comorbidities

• Obstructive sleep apnea: fatigue, headache
• Osteoarthritis: pain, decreased mobility
• Depression: decreased activity and motivation
• Balance problems
• Generalized weakness
• Cognitive deficits

Gerber, Clin Liver Dis, 2014.

Prescription for exercise: behavioral strategies

• Motivation
• Attainable
• Measurable
• Memory
• Positive thoughts
• Reinforcement
• Environmental support
• Stress management
• Social support
• Problem solve

Gerber, Clin Liver Dis, 2014.

Weight loss thresholds and impact on NAFLD

Treatment of NASH: Pharmacotherapy

• Currently available
• Vitamin E, pioglitazone (PIVENS trial; NEJM 2011)
• Potentially available in the future
• Obeticholic acid
• Elafibranor
• Cenicriviroc
• Many others in phase 2/3 trials

Histologic Improvement in NASH*

5 10 15 20 25 30 35 40 45 50 Vit E Placebo Pioglitazone

% Improved

P = 0.001 P = 0.04

*Decrease in NAS by ≥ 2 pts with ≥1 pt decrease in ballooning.

43% 34% 19%

Study included only non-diabetics

Obeticholic acid improves fibrosis in NASH

Younossi, Lancet, 2019.

Liraglutide (LEAN trial)

20 40 60 80 100 Liraglutide Placebo

*

• RCT, Liraglutide (n=23) vs placebo (n=22)
• Primary outcome: resolution of NASH without worsening of fibrosis.

* *

*p<0.05

% of patients

Armstrong, Lancet, 2016.

NAFLD pathways/targets for treatment

Rotman, Gut, 2017.

Treatment of Metabolic Syndrome in NAFLD

• Statins
• Safe for use in NAFLD
• Potential benefits of NAFLD/liver enzyme improvement and

reduced risk of liver death or HCC

• Not proven in randomized controlled trials
• Metformin
• Safe for use in NAFLD
• Some studies show improvement in liver biopsy and liver enzymes
• Not proven in randomized controlled trials
• Possible anti-neoplastic effects

NAFLD: shared management between primary care and hepatology

Brandman, Clinical Liver Disease, 2019.

Questions

• When should I suspect NAFLD?
• How do I diagnose NAFLD?
• What do I have to worry about in patients with NAFLD?
• What are the treatment options for NAFLD?
• Should I screen patients for NAFLD?

Summary

• NAFLD is common, and most patients with metabolic syndrome

comorbidities will have NAFLD, with ~16 million in the US having NASH

• NAFLD is an umbrella term that includes NAFL and NASH
• NASH>>>NAFL has risk of progression to cirrhosis
• Biopsy is needed to characterize NAFLD
• Management hinges on weight loss, exercise, avoiding added

carbohydrates, metabolic syndrome control

• Vitamin E only for biopsy-proven NASH
• Many drugs in the pipeline for NASH and fibrosis

Thank you!

Danielle.Brandman@ucsf.edu