updates in nonalcoholic fatty liver disease (nafld) · 2020-06-12 · danielle brandman, md, mas....
TRANSCRIPT
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Danielle Brandman, MD, MASProgram Director, Transplant Hepatology FellowshipDirector, UCSF Fatty liver clinicAssociate Professor of Medicine
Updates in Nonalcoholic Fatty Liver Disease (NAFLD)
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Disclosures
Allergan, Gilead, NGM, Grifols: Research funding, clinical trials
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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?
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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?
![Page 5: Updates in Nonalcoholic Fatty Liver Disease (NAFLD) · 2020-06-12 · Danielle Brandman, MD, MAS. Program Director, Transplant Hepatology Fellowship. Director, UCSF Fatty liver clinic](https://reader036.vdocuments.net/reader036/viewer/2022081405/5f0b08a97e708231d42e8624/html5/thumbnails/5.jpg)
NAFLD: worldwide epidemic
Younossi, Nat Rev Gastroenterol Hepatol, 2017.
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Epidemiology
Prevalence of NAFLD: ~30% US population
Prevalence of NASH: 3-5% US population
Farrell, Hepatology, 2006.Younoussi, Hepatology, 2015.
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Epidemiology
Prevalence of NAFLD: ~30% US population
Prevalence of NASH: 3-5% US population
Farrell, Hepatology, 2006.Younoussi, Hepatology, 2015.
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NAFLD
NAFLSteatosiswithout
inflammation
NASHSteatosis +
inflammation
NASH +
fibrosis
Cirrhosis
HCC
NAFLD: Non-Alcoholic Fatty LiverSpectrum of disease
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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?
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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
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What further work-up is needed?
A. Liver biopsyB. Counsel her on lifestyle modification to try to lose weight and
repeat liver tests again in 6 monthsC. Evaluate for other causes of chronic liver diseaseD. Transient elastography (Fibroscan)
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What further work-up is needed?
A. Liver biopsyB. Counsel her on lifestyle modification to try to lose weight and
repeat liver tests again in 6 monthsC. Evaluate for other causes of chronic liver diseaseD. Transient elastography (Fibroscan)
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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)
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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
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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
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NAFLDA 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
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Fibrosis progression
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Fibrosis progression is different in NASH vs NAFL
NASH7 years per 1 stage
~28 years 0 cirrhosis
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Fibrosis progression is different in NASH vs NAFL
NASH7 years per 1 stage
~28 years 0 cirrhosis
NAFL14 years per 1 stage
~56 years 0 cirrhosis
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What is the best way to classify patients with NAFLD?
A. Liver biopsyB. Fibroscan (transient elastography)C. MR elastographyD. FIB-4
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What is the best way to classify patients with NAFLD?
A. Liver biopsyB. Fibroscan (transient elastography)C. MR elastographyD. FIB-4
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Liver biopsy
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The liver biopsy is alive and kicking
Liver biopsy
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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
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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
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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.
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Serial use of NFS/FIB-4 and TE
Petta, AP&T, 2017.
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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?
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Prognosis of NAFLD by fibrosis stage
Steatosis
NASH ±F1−F2fibrosis
HCC
Death/LTx Cirrhosis
AdvancedF3fibrosis
12−40%
5−10%
0−50%
8%
13%
25−50%
14%
25%
7%
Day, J Hep, 2008.
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What is the strongest predictor of outcomes in patients with NAFLD?
A. Steatosis (fat) severityB. Liver sizeC. Fibrosis stageD. Number of ballooned hepatocytes on liver biopsy
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What is the strongest predictor of outcomes in patients with NAFLD?
A. Steatosis (fat) severityB. Liver sizeC. Fibrosis stageD. Number of ballooned hepatocytes on liver biopsy
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Fibrosis is the most important predictor of death and liver-related events
Hagstrom, J Hep, 2017.
Overall mortality
Liver-related event
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Outcomes in NAFLD with F3-4 fibrosis
Decompensation
CV events Non-HCCmalignancy
HCC
Vilar-Gomez, Gastro, 2018.
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Increased risk of incident CV in NAFLD
Hagstrom, J Hep, 2018.
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NAFLD is a risk factor for CVD
Targher, J Hepatol, 2016.
Fatal CVD EventsOR 1.31 (95% CI 0.87-1.97)
Fatal+non-fatal CVD EventsOR 1.63 (95% CI 1.06-2.48)
Non-fatal CVD EventsOR 2.52 (95% CI 1.52-4.18)
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NAFLD is a risk factor for CVDNAFLD + elevated GGT or advanced fibrosis
Targher, J Hepatol, 2016.
Fatal CVD EventsOR 3.28 (95% CI 2.26-4.77)
Fatal+non-fatal CVD EventsOR 1.94 (95% CI 1.17-3.21)
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Younossi, Hepatology, 2015.
Association of NAFLD and HCC
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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.
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2
NASH is a leading indication for LT
Noureddin, AJG, 2018.
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LT for NASH-HCC is expected to rise more steeply than NASH alone
Shingina, Transplantation, 2019.
HCC No HCC
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LT for NASH-HCC is expected to rise more steeply than NASH alone
Shingina, Transplantation, 2019.
HCC No HCC
NASH HCVFemale 36% 21%Age 62 57
NASH HCVFemale 51% 30%Age 58 52
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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?
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What treatment options are currently available to treat NAFLD?
A. Bariatric surgeryB. Vitamin EC. UrsodiolD. Lifestyle modification for weight lossE. B & D
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What treatment options are currently available to treat NAFLD?
A. Bariatric surgeryB. Vitamin EC. UrsodiolD. Lifestyle modification for weight lossE. B & D
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NAFLD treatment: Weight Loss
• Diet & Exercise Combination is best Avoid fructose-sweetened beverages,
added sugars Exercise alone reduces liver fat
o Aerobic >150-250 minutes per weeko Resistance training 45 minutes/day x 3
days/week
Harrison. Hepatology, 2009.Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015Chalasani , Hepatology 2012 .
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Oh, Hepatology, 2015.
21
44
68
*
** **
*p<0.05, **p<0.01
Moderate or vigorous exercise reduces visceral adiposity
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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
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Barriers to exerciseAssociated 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.
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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.
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Weight loss thresholds and impact on NAFLD
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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
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Histologic Improvement in NASH*
05
101520253035404550
Vit E Placebo Pioglitazone
% ImprovedP = 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
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Obeticholic acid improves fibrosis in NASH
Younossi, Lancet, 2019.
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Liraglutide (LEAN trial)
0
20
40
60
80
100
LiraglutidePlacebo
*• RCT, Liraglutide (n=23) vs placebo (n=22)• Primary outcome: resolution of NASH without worsening of fibrosis.
**
*p<0.05
% o
f pat
ient
s
Armstrong, Lancet, 2016.
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NAFLD pathways/targets for treatment
Rotman, Gut, 2017.
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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
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NAFLD: shared management between primary care and hepatology
Brandman, Clinical Liver Disease, 2019.
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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?
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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