nafld and nash - american college of...

Brent A. Tetri, MD, FACG

NAFLD and NASH

Brent A Tetri, MD, FACGSaint Louis UniversitySaint Louis University

Prevalence of NAFLD

NAFLD by u/s: 46%• Adults seen in medicine clinic• Screening colonoscopy• n = 156 134 biopsied (86%)

Williams et al, Gastroenterology 2011;140:124-31

p ( )

Liver Biopsy

ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology

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Prevalence of NASH by biopsy

NASH: 12% of total(30% of those with NAFLD)

Williams et al, Gastroenterology 2011;140:124-31

NASH as an indication for transplant

*

*PN = Probable NASH based on risk factorsBrandman et al, AASLD 2011


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NAFLD Activity Score (NAS)Grade 1 Grade 1 Grade 1

Grade 3 Grade 3Grade 2

Steatosis Ballooning Inflammation

MDB

Courtesy of EM Brunt

NAFLD Activity Score (NAS)Grade 1 Grade 1 Grade 1

Grade 3 Grade 3Grade 2

NAS = Steatosis + Ballooning + Inflammation• Not a weighted score (ie, maybe ballooning

should be weighted more)• Designed for clinical trials• Not designed to diagnose NASH

NAS = Steatosis + Ballooning + Inflammation• Not a weighted score (ie, maybe ballooning

should be weighted more)• Designed for clinical trials• Not designed to diagnose NASH

Steatosis Ballooning Inflammation

MDB

Courtesy of EM Brunt

g g• Fibrosis is staged separately (0 to 4)

g g• Fibrosis is staged separately (0 to 4)


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Assessing fibrosis: Fibroscan

• Measures shear wave velocity through the liver• Approved by FDA April 2013

ControlledPulse

Fibroscan: Shear wave propagation map

2525 mm

Depth 65 mmh

Time

65 mm


4



2525 mm

Depth 65 mmh

Time

65 mm


2525 mm

Depth 65 mm

d

t

Velocity = d/t

h

Time

65 mmt


5



2525 mm

Depth 65 mm

d

t

Velocity = d/tEquivalent stiffness (E, kPa)

E = 3pVs2

h

Time

65 mmt


• Examples, E (kPa):

4.1 kPa 5.5 kPa

Normal

26.3 kPa 36.3 kPa

Cirrhosis


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307 patients with NAFLD• Liver stiffness (E) in• Liver stiffness (E) in

controls = NAFLD without fibrosis

• Excellent prediction of advanced fibrosis

E =

Kumar et al, Dig Dis Sci 2013;58:265-274


AUROC

AdvancedFibrosis

0.94

Kumar et al, Dig Dis Sci 2013;58: 265-274

(Fibroscan)

Fibrosis


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P th iPathogenesisand

Treatment

Liver fat metabolism:Liver fat metabolism:

Hepatocellularfree fatty acids

Peroxisomalβ-oxidation

Mitochondrialβ oxidation

SER (P450)ω-oxidation

Triglyceride

VLDL(secreted)

β-oxidation

Lipiddroplets

(steatosis)


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Excesscarbohydrates

Excess peripheral lipolysis

Increased

Insulin resistance

Diet,uncontrolled

diabetesLiver fat metabolism:Liver fat metabolism:


De novolipogenesis

c easedcirculatingfatty acids




Triglyceride

VLDL(secreted)

β-oxidation

Lipiddroplets

(steatosis)

Excesscarbohydrates

Increased

Insulin resistance

Diet,uncontrolled

diabetesLipotoxicity hypothesis:Lipotoxicity hypothesis:


Lipotoxicmetabolites




De novolipogenesis

• ER stress



Lipiddroplets

(steatosis)

β-oxidationTriglyceride

VLDL(secreted)

ER stress• Inflammation• Apoptosis• Necrosis

Neuschwander-Tetri BA. Hepatology 2010;52:774-788

NASH


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Excesscarbohydrates

Increased

Insulin resistance

Diet,uncontrolled







De novolipogenesis

• ER stress



Lipiddroplets

(steatosis)


VLDL(secreted)



NASH

Excesscarbohydrates

Increased

Insulin resistance

Diet,uncontrolled



• Ceramides• Diacylglycerols• Lysophosphatidyl choline





De novolipogenesis

• ER stress



• Lysophosphatidyl choline• Others

Lipiddroplets

(steatosis)


VLDL(secreted)



NASH


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Excesscarbohydrates

Increased

Insulin resistance

Diet,uncontrolled







De novolipogenesis

• ER stress



Lipiddroplets

(steatosis)


VLDL(secreted)



NASH

Excesscarbohydrates

Increased

Insulin resistance

Diet,uncontrolled

diabetesTreatment of NASHTreatment of NASH Excess peripheral

lipolysis

• Weight loss• Exercise• TZDs?

Divert to muscle

• Cut the carbs!

Divert to muscle• Exercise





De novolipogenesis

• ER stress



Divert to muscle• Exercise

Diminish toxicity• Vitamin E?

Lipiddroplets

(steatosis)


VLDL(secreted)



NASH

Facilitate storage/secretion• Betaine?

• Fish oil?• Ursodiol?


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NASH CRN PIVENS trial

• Pioglitazone vs Vitamin E vs Placebo in adults– Pioglitazone

• PPARγ ligand• Improves adipocyte function

– Vitamin E• Antioxidant• Other mechanisms of action?

• Excluded diabetics, cirrhotics

Vitamin E alone met the pre-specified primary endpoint

50%) P< 0.001 P< 0.04

10

20

30

40

ortio

n of

sub

ject

s (

36/84NNT=4.4

26/80NNT= 6.6

16/83

Vit E placebo Pio0

10

treatment groups

Prop

o

N Engl J Med (2010) 362:1675-1685


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Both vitamin E and pioglitazone increased the proportion of subjects with resolution of NASH

100%

)

20

40

60

80

rtio

n of

sub

ject

s (%

P< 0.0008 P< 0.01

44/84 40/80

Vitamin E placebo pioglitazone0

20

study groups

prop

or 23/83

N Engl J Med (2010) 362:1675-1685

Liver enzymes

0

ALT

-40

-30

-20

-10

Ch

ange

(U

/L)

0 24 48 72 960 24 48 72 96

Weeks

Placebo Vitamin E Pioglitazone

N Engl J Med (2010) 362:1675-1685


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Change in body weight

5

WEIGHT

-2.5

02

.5

Cha

nge

(kg)

0 24 48 72 96

Weeks

Placebo Vitamin E Pioglitazone

N Engl J Med (2010) 362:1675-1685

PIVENS: weight changes and treatment

• Both weight change and

Vitamin E

Placebo • Both weight change and vitamin E treatment influenced change in NAS

• Weight loss + vitamin E was best

Hoofnagle et al, APT 2013;38:134-143


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Exercise

• 45 sedentary obese teen boys• All received nutritional advice• All received nutritional advice• 15: no exercise plan• 15: supervised wt lifting 3

times weekly for 3 months• 15: supervised

treadmill/ellipitical 3 times weekly for 3 monthsweekly for 3 months

• Conclusion: both forms of exercise decrease liver lipid

Lee et al, Diabetes 2012;61:2787-2795

Treatment of NASH 2013

• Focus on preventing adipose IR and associated systemic lipotoxicity– Doing this treats NASH and comorbidities

• Lifestyle modification– Exercise: Goal of 30-45 minutes aerobic + resistance

exercise daily– Weight loss

• gradual and sustained• bariatric surgery an option• bariatric surgery an option

– Healthy eating• portion control• avoid sugar sweetened beverages• no trans-fats


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Treatment of NASH 2013

• Drugs– Vitamin E

• 400 IU/d of natural form• Benefit in cirrhotics and diabetics unknown

– Thiazolidinediones? (pioglitazone, rosiglitazone)– Statins?– Metformin-no benefit of improving hepatic insulin

sensitivity• Benefit of controlling co morbidities on NASH?• Benefit of controlling co-morbidities on NASH?

– Recognize and treat obstructive sleep apnea– Treating hyperlipidemia, improving glycemic control: no

effect on liver• Treatment trials


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