Nonalcoholic Fatty Liver Disease
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Transcript of Nonalcoholic Fatty Liver Disease
Nonalcoholic Fatty Liver Disease
Stephanie H. Abrams, MD, MSAssistant Professor of Pediatrics
Baylor College of MedicineMedical Director-Kamp K’aana
NASH: a typical case 57 year old white female with elevated LFTs in
2008 No symptoms; history of obesity, type 2
diabetes, hypertension, hyperlipidemia, depression/anxiety
Meds: metformin, olmesartan/HCTZ, thyroxine, alprazolam, metoprolol, sertraline, clonidine, vitamins
SH: Occasional alcohol; nonsmoker PE: BMI 41 kg/m2
Lab: ALT 77, AST 81, AP 179, T bili 0.3, gluc 199, plts 168, INR 1.1
NASH: a typical case
Liver biopsy: NASH, NAS 4, stage 2 with extensive periportal fibrosis Plan: weight loss, exercise Follow up at 6 months: "No
symptoms"; "working on wt loss" PE: weight down 3 lbs/6 months
NASH: a typical case Admitted after no follow up x 2 years
Increased abdominal girth, dyspnea, leg edema
Wt up 60 lbs in 6 weeks Minor MVA with confusion Interim diagnosis: obstructive sleep apnea PE: Ascites, 3+ leg edema, alert/oriented Lab: ALT 55, AST 102, Alb 2.6, INR 1.7,
MELD 15, plts 149 CT: nodular liver, splenomegaly,
perisplenic varices, moderate ascites
NASH: a typical case Abdominal CT:
NASH: a typical case
Summary: Progression of NASH to cirrhosis
in setting of obesity, DM2, HTN Near normal liver enzymes
Prevalence of NAFLD in Adults NAFLD was present in 46% of all subjects by ultrasound (n=400)
74% of diabetics
Prevalence higher in men (58.9%)
Most common in Hispanics (58.3%), Caucasians (44.4%), African Americans (35.1%)
NAFLD patients: Were more likely to have HTN, higher BMI, & DM Ate more fast food & exercised less
NASH present in 12.2% of all adults Present in 22.2% of diabetics Advanced fibrosis in 22.5% 30% of all of those with NAFLD
Williams CD, et al. Gastroenterology 2011; 140: 124-131
NASH: 12%
Prevalence of NAFLD in Children Fatty liver was present in 13% of all subjects
Prevalence higher in boys (11.1%) compared with girls (7.9%)
Prevalence increases with age 17.3% for ages 15-19 years
NASH present in 3% of all children
Schwimmer, et al. Pediatrics 2006
Schwimmer, et al. Schwimmer, et al. Pediatrics Pediatrics 20062006
Prevalence of Fatty Liver by Race/Ethnicity
0
5
10
15
Black White Asian Hispanic
Pe
rce
nta
ge
•Using a logistic regression model, the Using a logistic regression model, the odds ratio for the presence of fatty odds ratio for the presence of fatty liver in Hispanics was 5.0liver in Hispanics was 5.0
NASH as an indication for transplant
*PN = Probable NASH based on risk factorsBrandman et al, AASLD 2011
*
Primary Diagnoses for Patients Transplanted in 2006
05
1015
20253035
Hepat
itis
C
Alcoho
lic C
irrhos
is
NASH
Crypt
ogenic
Cirr
hosis
PSC
Biliar
y Cirr
hosis
Other
Cirr
hosi
s
Met
abolic
Dis
ease BA
Retra
nspla
nt G
raft
Failu
re
Mal
ignan
cy
Other
Pe
rce
nt
NASH Accounted for 10.3% of all Liver Transplantation at the Cleveland Clinic in 2006
10.3%12.8%
33.1%
www.clevelandclinic.org
Pathogenesis: new ideas
“Two hit” vs lipotoxicity
Triglyceride
VLDL(secreted)
Hepatocellularfree fatty
acids
B Tetri
De novolipogenesis
Excesscarbohydrates
Excess peripheral lipolysis
Increasedcirculatingfatty acids
Insulin resistanc
e
Diet,uncontrolleddiabetes
Liver fat metabolism:Liver fat metabolism:
Lipiddroplets
(steatosis)
Triglyceride
VLDL(secreted)
Hepatocellularfree fatty
acids
NASH
B Tetri
Peroxisomalβ-oxidation
Mitochondrialβ-oxidation
SER (P450)ω-oxidation
ROS
ROS = reactive oxygen species
“Two-hit” hypothesis:“Two-hit” hypothesis:
De novolipogenesis
Excesscarbohydrates
Increasedcirculatingfatty acids
Insulin resistanc
e
Diet,uncontrolleddiabetes
Excess peripheral lipolysis
1
2
Lipotoxicmetabolites
Peroxisomalβ-oxidation
Lipiddroplets
(steatosis)
Mitochondrialβ-oxidation
Triglyceride
SER (P450)ω-oxidation
VLDL(secreted)
De novolipogenesis
Excesscarbohydrates
• ER stress• Inflammation• Apoptosis• Necrosis
Hepatocellularfree fatty acids
Increasedcirculatingfatty acids
Insulin resistance
Diet,uncontrolleddiabetes
B Tetri
Lipotoxicity hypothesis:Lipotoxicity hypothesis:
Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
Excess peripheral lipolysis
NASH
Lipotoxicmetabolites
Peroxisomalβ-oxidation
Lipiddroplets
(steatosis)
Mitochondrialβ-oxidation
Triglyceride
SER (P450)ω-oxidation
VLDL(secreted)
De novolipogenesis
Excesscarbohydrates
• ER stress• Inflammation• Apoptosis• Necrosis
Hepatocellularfree fatty acids
Increasedcirculatingfatty acids
Insulin resistance
Diet,uncontrolleddiabetes
B Tetri Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
Excess peripheral lipolysis
NASH
• Ceramides• Diacylglycerols• Lysophosphatidyl choline• Others
Lipotoxicity hypothesis:Lipotoxicity hypothesis:
Lipotoxicmetabolites
Peroxisomalβ-oxidation
Lipiddroplets
(steatosis)
Mitochondrialβ-oxidation
Triglyceride
SER (P450)ω-oxidation
VLDL(secreted)
De novolipogenesis
Excesscarbohydrates
• ER stress• Inflammation• Apoptosis• Necrosis
Hepatocellularfree fatty acids
Increasedcirculatingfatty acids
Insulin resistance
Diet,uncontrolleddiabetes
B Tetri
Treatment of NASHTreatment of NASH
Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
Excess peripheral lipolysis
NASH
• Weight loss• Exercise• TZDs?
Divert to muscle• Exercise
• Cut the carbs!
Facilitate storage/secretion
• Betaine?
Diminish toxicity
• Vitamin E?• Fish oil?• Ursodiol?
Divert to muscle• Exercise
NASH and the Metabolic Syndrome
NASH
Bad diet+
Obesity+
Sedentary+
Geneticpredisposition
Excesscirculating
NEFALipotoxic
intermediatesin the liver
Increasedliver triglyceride Steatosis
IR
NEFA: nonesterified fatty acids, ie, free fatty acidsIR: insulin resistancePCOS: polycystic ovary syndrome
β-oxidation
NASHRenin-
angiotensinactivation
DiabetesHyperinsulinemiaPCOS
HypertriglyceridemiaHypercholesterolemia
Cancer
Sleepapnea
Excesscirculating
NEFA
Lipotoxicintermediatesin the liver
Increasedliver triglyceride Steatosis
IR
NEFA: nonesterified fatty acids, ie, free fatty acidsIR: insulin resistancePCOS: polycystic ovary syndrome
β-cellloss
HTN
β-oxidation
Vascular disease
CAD/PVD
Bad diet+
Obesity+
Sedentary+
Geneticpredisposition
NASH and the Metabolic Syndrome
Treatment of NASH Lifestyle modification remains the
primary treatment recommendation Neuschwander-Tetri, B. A. Lifestyle modification as the primary
treatment of NASH. Clinics in Liver Disease (2009) 13: 649-665 Harrison, S. A. and Day, C. P. Benefits of lifestyle modification in
NAFLD. Gut (2007) 56: 1760-1769. Sullivan, S. Implications of diet on nonalcoholic fatty liver disease. Curr
Opin Gastroenterol (2010) 26: 160-164.
Bariatric surgery Pillai, A. A. and Rinella, M. E. Non-alcoholic fatty liver disease: is
bariatric surgery the answer? Clinics in Liver Disease (2009) 13: 689-710.
Drugs Ratziu, V. and Zelber-Sagi, S. Pharmacologic therapy of non-alcoholic
steatohepatitis. Clinics in Liver Disease (2009) 13: 667-688. Trial results
NASH CRN PIVENS trial
Pioglitazone vs Vitamin E vs Placebo in adults
Excluded diabetics, cirrhotics
PIVENS Study Design
placebo
Pioglitazone (30 mg/day)
Vitamin E (rrr α-tocopherol) 800 IU/day
RandomizationEligibility assessed by local pathologist
(1:1:1)Wk 0
Month -6
End of treatmentLiver Biopsy
Wk 96
Week 120end of study
Liver biopsy
N Engl J Med (2010) 362: 1675-1685
PIVENS Primary endpoint:
Decrease in NAS by 2 or more points, with at least a 1 point drop in ballooning, and no worsening of fibrosis
2 Primary comparisons: Vitamin E vs placebo Pioglitazone vs placebo
Significance set at p< 0.025
Secondary endpoints: changes in individual histologic features resolution of steatohepatitis changes in anthropometrics, insulin resistance, quality of life adverse events
N Engl J Med (2010) 362: 1675-1685
Vitamin E alone met the pre-specified primary endpoint
Vit E placebo Pio0
10
20
30
40
50
treatment groups
Pro
po
rtio
n o
f su
bje
cts
(%) P< 0.001 P< 0.04
36/84NNT=4.4
26/80NNT= 6.6
16/83
Both vitamin E and pioglitazone increased the proportion of subjects with resolution of NASH
Vitamin E placebo pioglitazone0
20
40
60
80
100
study groups
pro
po
rtio
n o
f su
bje
cts
(%)
P< 0.0008 P< 0.01
44/84
23/83
40/80
N Engl J Med (2010) 362: 1675-1685
Liver enzymes
-40
-30
-20
-10
0
Ch
an
ge
(U
/L)
0 24 48 72 96
Weeks
Placebo Vitamin E Pioglitazone
ALT
N Engl J Med (2010) 362: 1675-1685
Change in body weight
-2.5
02
.55
Ch
an
ge
(kg
)
0 24 48 72 96
Weeks
Placebo Vitamin E Pioglitazone
WEIGHT
N Engl J Med (2010) 362: 1675-1685
Who should we treat with vitamin E? Should we look for low vitamin E levels? Does reduction in the ALT mean the patient is
responding?
Who should we treat with vitamin E?
Loomba et al, AASLD 2010
Vit E treated
• Responders didn’t have low initial vitamin E levels
• The increase in vitamin E did not correlate with response
• Non-compliance did not explain non-response
Who should we treat with vitamin E?
Loomba et al, AASLD 2010
Placebo
• Responders didn’t have low initial vitamin E levels
• The increase in vitamin E did not correlate with response
• Non-compliance did not explain non-response
Vit E treated
Who should we treat with vitamin E?
Loomba et al, AASLD 2010
• ALT dropped a bit more in responders than placebo
• ALT dropped in both responders and non-responders
Responders
Non-responders
P = 0.005
PIVENS trial summary
Vitamin E helped in about half the patients Non-cirrhotic, non-diabetic Natural vitamin E, 800 IU/day We don’t know why it works We can’t predict who will respond or who is
responding Pioglitazone helped a bit less that half the
patients Non-cirrhotic, non-diabetic Weight gain is a problem Long-term safety is still an issue
NASH CRN TONIC trial
Treatment of NAFLD in Children = TONIC NASH Clinical Research Network study Hypothesis: metformin and vitamin E are
superior to placebo for the treatment of NAFLD
Lavine et al, JAMA (2011) 305: 1659-1668
TONIC trial Multicenter, double masked, double placebo,
randomized
Metformin 500 mg bid + vitamin E placebo
orVitamin E (natural form) 400 IU bid + metformin
placeboorBoth placebos bid
Treatment duration: 2 years A priori endpoint: change in ALT Secondary endpoint: histology
Lavine et al, JAMA (2011) 305: 1659-1668
TONIC: changes in primary endpoint (ALT)
Metformin
Placebo
Vitamin E
ALT
Lavine et al, JAMA (2011) 305: 1659-1668
TONIC: changes in primary endpoint (ALT)
Metformin
Placebo
Vitamin E
ALT
No significant differences
Lavine et al, JAMA (2011) 305: 1659-1668
Vitamin E increased resolution of NASH(from initial definite or borderline NASH)
TONIC results: Liver biopsy changes
Lavine et al, JAMA (2011) 305: 1659-1668
% with resolution of NASH
P = 0.006N.S.
TONIC trial summary Vitamin E helped about half the children
Primary endpoint of ALT change not met (placebo improved)
Biopsies did improve 800 IU of natural vitamin E daily
Metformin did not help
Lavine et al, JAMA (2011) 305: 1659-1668
Treatment of NASH 2011 Focus on preventing adipose IR and
associated systemic lipotoxicity Doing this treats NASH and comorbidities
Lifestyle modification Exercise: Goal of 30-45 minutes aerobic daily Weight loss
gradual and sustained bariatric surgery an option
Healthy eating portion control avoid sugar sweetened beverages no trans-fats
Treatment of NASH 2011 Drugs
Vitamin E? Thiazolidinediones? (pioglitazone, rosiglitazone) Statins? Metformin-no benefit of improving hepatic insulin
sensitivity Not effective: ursodiol, betaine
Benefit of controlling co-morbidities on NASH? Recognize and treat obstructive sleep apnea Treating hyperlipidemia, improving glycemic
control: no effect on liver
Future directions
Incretin mimetics? Naturally occurring: GIP, GLP-1
Made by enteroendocrine L-cells Responsible for 70% of post-prandial insulin secretion Delays gastric emptying, increases satiety Peripheral effects?
Analogue: exenetide Inhibit breakdown by inhibiting DPP-4: gliptins
(sitagliptin, saxagliptin) FXR ligands?
Farnesoid X receptor = nuclear receptor activated by bile acids
FXR agonist for NASH
FXR = “Farnesoid X receptor” = ligand activated nuclear receptor
Bile acids are the major natural ligands Increased bile acids decreased synthesis,
increased export
FXR agonist for NASH
BA
Cholesterol
BA
Gut
BABA = Bile acids
FXR agonist for NASH
BA
Cholesterol
BA
Gut
BA
FGF19 synthesis
by enterocytes
BA = Bile acids
FGF=Fibroblast growth factor
FXR = Farnesoid X receptor
FXR
BA + FXR
Exporters(MDRs, BSEP)
TGR5Bile acid receptor
Hepatic and peripheral effects
Regulation of gene expression by FXR
Neuschwander-Tetri, B. A. Curr Gastroenterol Rep (2012) 14: 55-62
FXR agonist for NASH
High affinity FXR ligand
Research options at SLU NASH Clinical Research Network studies
NASH CRN treatment trials FLINT (FXR Ligand in the Treatment of NASH) Enrolling now!
“Database” observational study, seeking: Ideally patients suspected of having NAFLD but not
yet biopsied Can enroll with a biopsy < 3 months old Annual visits with free lab tests until 2014
Pathogenesis of NASH: A Two “Hit” Hypothesis
Festi, et al. Ob Rev. 2004; 5: 27- 42
2nd Hit
FFAsLipid PeroxidationROSScavengers
TNF ATPIKK NF-kEndotoxin IL-6
OBESITY DyslipidemiaType 2 Diabetes
FFAsHyperinsulinemiaInsulin sensitivityLeptin sensitivityAdiponectin effectFAT STORAGE 1st Hit
InflammationNecrosisApoptosis
LeptinLPO end productsTNF
HSCs activation
FIBROSIS
Day CP. Liver International 2006
Fibrosis &
cirrhosis
Steatosis
Steatohepatitis
Normal
Genes
Environment
Oxidative Stress,
cytokine, & endotoxin
related genes
Steatosis genes
Fibrosis genes
Environmental Factors Alcohol intake
Low is protective Dietary factors Low antioxidant
vitamins saturated fat
Obesity * Food intake Lack of exercise Type II DM* Small bowel
bacterial overgrowth Sleep apnea
syndrome
*Have a genetic component*Have a genetic component
Wilfred de Alwis, NM & CP Day Wilfred de Alwis, NM & CP Day Seminars Liv dsSeminars Liv ds. . 20072007
Hypothesis
Both pioglitazone and vitamin E are superior to placebo for the treatment of NASH.
NASH CRN
Specific Aim To perform a prospective multicenter,
double-masked, double-placebo, randomized clinical trial of pioglitazone (30 mg/day) or vitamin E (rrr α tocopherol 800 IU/day) versus placebo pioglitazone provided by Takeda
under a CRADA vitamin E provided by Pharmavite
under a clinical trials agreement
NASH CRN
Inclusion and exclusion criteria Inclusion criteria:
Alcohol consumption < 20 gm/day for women and 30 gm/day for men
Biopsy proven steatohepatitis within last 6 months
NAFLD activity score: ≥ 5 with definite or
probable steatohepatitis =4 + definite
steatohepatitis agreed by 2/3 pathologists
Exclusion criteria: Diabetes mellitus Cirrhosis Prior bariatric surgery Any drug therapy for
NASH between biopsy and randomization
Presence of other liver diseases
NASH CRN
Study Design
placebo
Pioglitazone (30 mg/day)
Vitamin E (rrr α-tocopherol) 800 IU/day
RandomizationEligibility assessed by local pathologist
(1:1:1)Wk 0
Month -6
End of treatmentLiver Biopsy
Wk 96
Week 120end of study
Liver biopsy
NASH CRN
Plan of Analysis(all histologic analyses on blinded central review of deeper cuts of baseline liver
biopsy & end of treatment biopsy) Primary endpoint:
Decrease in NAS by 2 or more points, with at least a 1 point drop in ballooning, and no worsening of fibrosis
2 Primary comparisons of proportion of subjects who met endpoint: Vitamin E vs placebo Pioglitazone vs placebo
Significance set at p< 0.025
Secondary endpoints: changes in individual histologic features resolution of steatohepatitis changes in anthropometrics, insulin resistance, quality of life adverse events
NASH CRN
Baseline Characteristics
Means or %s
Vitamin E
N= 83
Placebo
N= 84
Pioglitazone
N= 80
Age (yrs)
Female (%)
Caucasian (%)
BMI (Kg/m2)
Waist circumference (cm)
AST (IU/L)
ALT (IU/L)
AP (IU/L)
Bilirubin (mg/dl)
Triglycerides (mg/dl)
IR (HOMA-IR)
46.6
61
66
34
107
59
86
77
0.7
166
5.2
45.4
58
81
35
109
55
81
82
0.7
165
5.5
47
59
74
34
108
54
82
86
0.7
162
5.0
NASH CRN
Baseline histology
Vitamin E
Mean or %
Placebo
Mean or %
Pioglitazone
Mean or %
Steatosis grade
Inflammation grade
Ballooning grade
Fibrosis stage
NAFLD activity score (NAS)
1.9
1.8
1.3
1.5
5.1
1.9
1.6
1.3
1.6
4.8
2
1.8
1.1
1.4
5
% without ballooning on central review of deeper cuts of baseline biopsy
18 17 27
blinded central review ofdeeper cuts of baseline liver biopsy
NASH CRN
Primary Outcome –Vitamin E alone met the pre-specified primary endpoint
Vit E placebo Pio0
10
20
30
40
50
treatment groups
Pro
po
rtio
n o
f su
bje
cts
(%)
P< 0.001 P< 0.04
36/84NNT=4.4
26/80NNT= 6.6
16/83
NASH CRN
Both Vitamin E and Pioglitazone improve steatosis
-40
-20
0
20
40
60
80
pro
po
rtio
n o
f su
bje
cts
(%)
wo
rsen
ed
i
mp
rove
d P< 0.001 P<0.0001
Vit E placebopioglitazone
Δ grade0.1
Improvement in severity of steatosis gradeVit E vs placebo: p< 0.0001Pio vs placebo: p< 0.0001
Δ grade0.7
Δ grade0.8
NASH CRN
Both Vitamin E and Pioglitazone improve lobular inflammation
-60
-40
-20
0
20
40
60
80
pro
po
rtio
n o
f su
bje
cts
(%)
wo
rsen
ed
im
pro
ved p< 0.01 p< 0.001
Vit Eplacebo
pioglitazone
Improvement in severity of inflammation:Vitamin E vs placebo: p< 0.008Pioglitazone vs placebo: p< 0.0009
Δ grade0.6
Δ grade0.2
Δ grade0.7
NASH CRN
Both Vitamin E and Pioglitazone improve the severity of ballooning and
the proportion of subjects whose ballooning improves
-60
-40
-20
0
20
40
60
80
pro
po
rtio
n o
f su
bje
cts
(%)
wo
rsen
ed
im
pro
ved
P<0.02 P<0.02
Vit Eplacebo
pioglitazone
Δ grade0.5
Δ grade0.4
Δ grade0.2
Improvement in severity (grade) of ballooning:Vit E vs placebo: p< 0.01Pioglitazone vs placebo: 0.03
NASH CRN
Both vitamin E and pioglitazone increased the proportion of subjects with
resolution of NASH
Vitamin E placebo pioglitazone0
20
40
60
80
100
study groups
pro
po
rtio
n o
f su
bje
cts
(%)
P< 0.0008 P< 0.01
44/84
23/83
40/80
NASH CRN
Mutually exclusive categorization of reasons for not meeting primary outcome
Categories
Vit E
N=48/84
Placebo
N=67/83
Pio
N=53/80
No follow up biopsy
Worsening of fibrosis score
Failure to improve NAS ≥ 2
Failure to meet primary outcome due to ballooning score=0 at baseline
4
15
22
7
11
16
35
5
10
12
20
11
NASH CRN
Neither Vitamin E nor Pioglitazone improved fibrosis scores or proportion of subjects with
improved fibrosis
-60
-40
-20
0
20
40
60
pro
po
rtio
n o
f su
bje
cts
(%)
wo
rsen
ed
i
mp
rove
d
Vitamin E placebopioglitazone
n.s. n.s.
Δ grade0.3 Δ grade
0.1
Δ grade0.4
Improvement in severity of fibrosis scores:Vit E vs placebo: p= 0.19 (n.s.)Pioglitazone vs placebo: p=0.1 (n.s.)
NASH CRN
Liver enzymes-4
0-3
0-2
0-1
00
Ch
an
ge
(U
/L)
0 24 48 72 96
Weeks
Placebo Vitamin E Pioglitazone
ALT
NASH CRN
Insulin resistance-1
01
Ch
an
ge
([m
g/d
L x
µU
/mL
]/4
05
)
0 48 96
Weeks
Placebo Vitamin E Pioglitazone
HOMA-IR
NASH CRN
Change in body weight-2
.50
2.5
5
Ch
an
ge
(kg
)
0 24 48 72 96
Weeks
Placebo Vitamin E Pioglitazone
WEIGHT
NASH CRN
Adverse eventsAdverse event Vitamin E Placebo Pioglitazone
Total SAE
Drug-related SAE
Deaths
ALT > 500 IU/l
Bili > 3 mg/dl
CVD events
New onset T2DM
Bone fractures
Bone ΔT > -1
7
0
1
0
1
12
4
3
0
10
0
0
0
0
12
0
5
0
2
0
0
0
2
10
0
3
1
NASH CRN
Summary -1 Vitamin E (800 IU/day), but not pioglitazone
(30 mg/day), was superior to placebo for histological improvement as defined in the primary outcome measure
Both vitamin E and pioglitazone significantly improved: Steatohepatitis Steatosis grade Inflammation grade NAFLD activity score
Neither drug improved fibrosis scores significantly
NASH CRN
Summary -2
Pioglitazone improved insulin sensitivity, but was associated with weight gain
There were no study drug related SAEs
NASH CRN
Vitamin E is superior to placebo for the treatment of active NASH in nondiabetic adult patients.
Pioglitazone did not meet the primary outcome for histological improvement, but significantly improved other key histological features of NASH.
Neither drug improved fibrosis Both agents were relatively safe over the 96
week study, although pioglitazone was associated with weight gain
Conclusions
NASH CRN
Treatment Of Nonalcoholic steatohepatitis In Children
(TONIC)
The NIDDK Clinical Research Network
(NASH CRN)
Hypothesis
Both metformin and vitamin E are superior to placebo for the treatment of NAFLD
NASH CRN
Specific Aim
To perform a multicenter, double-masked, double-placebo, randomized clinical trial of metformin (500mg BID) or vitamin E (RRR-a-tocopherol 400 IU BID) versus placebo for the treatment of NAFLD Over-encapsulated generic metformin/placebo Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Inclusion and exclusion criteria
Inclusion criteria: Boys & girls 8-17yo Biopsy proven NAFLD
within 6 mos ALT>60 U/L at
randomization and 1-12mos prior
Able to swallow pills Informed consent/assent Complete screening in
112 days
Exclusion criteria: Diabetes mellitus Cirrhosis Prior bariatric surgery Significant alcohol ALT>400 Presence of other liver
diseases Pregnancy/nursing Any drug tx for NASH in
the 3mos prior to randomization
NASH CRN
Hypothesis
Both metformin and vitamin E are superior to placebo for the treatment of NAFLD
NASH CRN
NASH CRN
Specific Aim
To perform a multicenter, double-masked, double-placebo, randomized clinical trial of metformin (500mg BID) or vitamin E (RRR-a-tocopherol 400 IU BID) versus placebo for the treatment of NAFLD Over-encapsulated generic metformin/placebo Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Primary Outcome-neither treatment met criterion for sustained ALT reduction
NASH CRN
Specific Aim
To perform a multicenter, double-masked, double-placebo, randomized clinical trial of metformin (500mg BID) or vitamin E (RRR-a-tocopherol 400 IU BID) versus placebo for the treatment of NAFLD Over-encapsulated generic metformin/placebo Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Vitamin E increased resolution of NASH
(from initial definite or borderline NASH)
NASH CRN
To perform a multicenter, double-masked, double-placebo, randomized clinical trial of metformin (500mg BID) or vitamin E (RRR-a-tocopherol 400 IU BID) versus placebo for the treatment of NAFLD Over-encapsulated generic metformin/placebo Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Neither Vitamin E nor Metformin Improved Fibrosis Score
Specific Aim
To perform a multicenter, double-masked, double-placebo, randomized clinical trial of metformin (500mg BID) or vitamin E (RRR-a-tocopherol 400 IU BID) versus placebo for the treatment of NAFLD Over-encapsulated generic metformin/placebo Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Final Conclusions NAFLD is the most common chronic liver
disease in the world & threatens our organ allocation system
Vitamin E, Pioglitazone, & Metformin do not improve fibrosis in NAFLD
Vitamin E improves ballooning and NAS scores in adults & children
Behavior modification & treatment of underlying obesity is imperative
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Demographics & physical characteristics (n=39)Parameters Mean
Gender 25 females14 males
Ethnicity 15 Whites12 Hispanics
11 Blacks1 Asian
Age (y) 11.9 ± 1.39*
Weight (kg) 88.8 ± 18.6
Height (cm) 159.8 ± 7.3
BMI (kg/m2) 34.6 ± 6.1
FFM (kg) 49.8 ± 9.3
FM (kg) 39.1 ± 13.0
FM (%) 43.2 ± 7.4
Wt z-score 2.65 ± 0.60
BMI z-score 2.38 ± 0.31
Wt percentile 98.8 ± 1.9
BMI percentile 98.9 ± 0.9
Changes in anthropometric & body composition post camp
-6
-5
-4
-3
-2
-1
0
1
2
3
P<0.01
P<0.01
P<0.01P<0.01
P<0.01
P<0.01
Fat(%)
Fat(kg)
FFM(kg)
BMIz-score
BMI
(kg/m2)Wt (kg)
Po
st C
am
p -
Pre
Ca
mp
Changes in IWQOL scores post camp
-5
0
5
10
15
20
P<0.01
P=0.60
P<0.03
P<0.01
P<0.02
TotalScore
FamilyRelations
SocialLife
BodyEsteem
PhysicalComfort
Po
st C
am
p -
Pre
Ca
mp
Changes in CDI scores post camp
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
P=0.94
Inte
rper
sona
l
Proble
ms
P<0.05
P=0.10
P=0.07
P=0.77P=0.51
Total
Score
Negat
ive
Self E
steem
Anhed
onia
Inef
fecti
vene
ss
Negat
ive
Moo
dP
ost
Ca
mp
- P
re C
am
p
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