updates in nonalcoholic fatty liver disease (nafld) · 2020-06-12 · danielle brandman, md, mas....

Danielle Brandman, MD, MASProgram Director, Transplant Hepatology FellowshipDirector, UCSF Fatty liver clinicAssociate 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?

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.

NAFLD

NAFLSteatosiswithout

inflammation

NASHSteatosis +

inflammation

NASH +

fibrosis

Cirrhosis

HCC

NAFLD: Non-Alcoholic Fatty LiverSpectrum of disease

Questions


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 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)

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

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

Fibrosis progression

Fibrosis progression is different in NASH vs NAFL

NASH7 years per 1 stage

~28 years 0 cirrhosis

Fibrosis progression is different in NASH vs NAFL

NASH7 years per 1 stage


NAFL14 years per 1 stage


What is the best way to classify patients with NAFLD?

A. Liver biopsyB. Fibroscan (transient elastography)C. MR elastographyD. 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


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.

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

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-HCCmalignancy

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 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)

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)

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 HCVFemale 36% 21%Age 62 57

NASH HCVFemale 51% 30%Age 58 52

Questions


What treatment options are currently available to treat NAFLD?

A. Bariatric surgeryB. Vitamin EC. UrsodiolD. Lifestyle modification for weight lossE. B & D

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 .

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 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.

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*

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

Obeticholic acid improves fibrosis in NASH

Younossi, Lancet, 2019.

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.

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


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!

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updates in nonalcoholic fatty liver disease (nafld) · 2020-06-12 · danielle brandman, md, mas....

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