stopnash r kohli new - naspghan · composition? 9 area under the curve altered enterohepatic...
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NASH : What’s Bile Got to Do With It?
Rohit Kohli, MBBS, MS
Associate Professor of Pediatrics
Gastroenterology, Hepatology, & Nutrition
DisclosuresI have the following relationships to disclose:
– Ethicon Endo Surgery Inc.– Galectin Pharmaceuticals– Synageva Biopharma/Alexion– Raptor Pharmaceuticals– Lumena/Shire
I will be discussing off‐label use of medications in my presentation
Background: Bariatric Surgery is a Treatment for ObesityWeight Loss Interventions
• Lifestyle
• Drug therapy
• Bariatric surgery0 1 2 3 4
-10
-8
-6
-4
-2
0Lifestyle
Time (years)
We
igh
t L
os
s (
%)
0 1 2 3 4-10
-8
-6
-4
-2
0LifestyleLifestyle+Orlistat
Time (years)
We
igh
t L
os
s (
%)
0 5 10 15-40
-30
-20
-10
0
LifestyleLifestyle+Orlistat
Time (years)
We
igh
t L
os
s (
%)
0 5 10 15-40
-30
-20
-10
0
LifestyleLifestyle+OrlistatBariatric Surgery
Time (years)
We
igh
t L
os
s (
%)
Annals of Surgery 222(3):339-501995 (1995)Diabetes Care 27(1):155-61 (2004)
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Severe NASH now considered indication for surgery in adolescents
Selection criteria for adolescent weight loss surgery
BMI Comorbidities
> 35 • Type 2 DM • moderate‐severe OSA (AHI ≥ 15 events/hr)• pseudotumor cerebri• severe NASH
> 40 • Mild OSA (AHI>5 events/hr)• HTN• Insulin resistance/IGT• Dyslipidemia• impaired QOL or ADL
Pratt, JSA et al. Obesity 2009; 17:901
But how does this “Bariatric Surgery”WORK to improve NASH?
Potential Mechanisms behind Bariatric Procedures
• Obvious
– Restriction
– Malabsorption
• Not so obvious
– Altered metabolic pathways/processes
• Increased energy expenditure
• Signaling for early satiation
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Restriction ?
Adjustable Gastric Banding
Vertical SleeveGastrectomy
Gastric Combination
Roux-en-Y Gastric Bypass
Malabsorption ?
Adjustable Gastric Banding
Vertical SleeveGastrectomy
Gastric Combination
Roux-en-Y Gastric Bypass
Potential Mechanisms behind Bariatric Procedures
• Obvious
– Restriction
– Malabsorption
• Not so obvious
– Altered metabolic pathways/processes
• Increased energy expenditure
• Signaling for early satiation
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Background: Bariatric SurgeryIncreases Fasting Serum Bile Acids
Body mass index is decreasing and, on the contrary, fasting total serum bile acid levels are increasing after bariatric surgery.
Metabolism 58(10):1400-7 (2009)
Bile Acids and Bariatric Surgery
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Effect of Bariatric Surgery onSerum Bile Acid Levels
Kohli et alJ Clin Endocrinol Metab. 98(4):E708-12. (2013)
Vertical Sleeve GastrectomyRoux-en-Y Gastric Bypass
RYGB Pre
Surg
ery
RYGB P
ost S
urger
y0
1
2
3
4
5*
Fa
sti
ng
To
tal
Se
rum
Bile
Ac
ids
(um
ol/L
)
Gastric Banding
LAGB Pre
Surg
ery
LAGB Post
Surg
ery
0
1
2
3 *
Fa
sti
ng
To
tal
Se
rum
Bile
Ac
ids
(um
ol/L
)
Kohli et alJ Clin Endocrinol Metab. 98(4):E708-12. (2013)
Steinart et alObesity [Epub ahead of print] (2013)
How can we study this BA phenomenon in Bariatric Surgery?
Normal Enterohepatic Circulation
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Altered Enterohepatic Circulation
?
Results: Change in Body Weight
* =p<0.05
10 20 30 40 50
-50
0
50
100ShamSham PFIT
*
Post Operative Day
Ch
ang
e in
Bo
dy
Wei
gh
t (G
ram
s)
Kohli et al Am J Physio; 299: G652-660, 2010
Results: Serum Bile Acids
Sham
Sham
PF IT
0
20
40
60
Fas
ting S
erum
Bile
Aci
d (
mole
/L)
******
***=p<0.001Kohli et al Am J Physio; 299: G652-660, 2010
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Bile diversion
Bile acid diversion Image Courtesy Jose Berger, MD
Body Weights
-4 0 4 8 12 16 20 24 28 32
460
480
500
520
540
560
580 Naive
Sham
BD
** ** ****
Bo
dy
Wei
gh
t (g
)
Bile Diversion
Kohli et al., Endocrinology, 2013 Apr 16.
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Fasting serum bile acid
Sham BD
0
20
40
60**
Bile
Ac
id(
M /
L)
Bile Diversion
Kohli et al., Endocrinology, 2013 Apr 16.
IT and BD Study ‐ Conclusions
• IT and BD surgery in rat models
– Reproduces the metabolic benefits of bariatric
surgery
– Loss of fat mass
– Improvement in insulin sensitivity
– Increases GLP‐1 and Serum Bile Acids
Do these procedures impact bile acidcomposition?
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Area Under the Curve
Altered Enterohepatic Circulation
?
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10
0 500 1000 1500 2000
Taurine
Glycine
IT
*
Sham PF
Serum Conjugated Bile Acids(ng/mL)
Results: Serum Bile Acids
Kohli et al Am J Physio; 299: G652-660, 2010
Bile Diversion
22%
33%*
14%
1%
3%
7%
1%
0%0%
9%
1%
2% 1%
3%3%
TMCA
TCA
TUDCA
T‐CDCA
TDCA
GCA
GUDCA
GCDCA
GDCA
CA
CDCA
DCA
α‐MCA
β‐MCA
H/UDCA
BD
Kohli et al., Endocrinology, 2013 Apr 16.
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So what about the“established”
bariatric procedures?
Vertical Sleeve Gastrectomy
Modified from Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
Results: body weight post surgery
0 7 14 21 28 35 42 60-15
-10
-5
0
5
10
15 HFD Naïve
Sham PFSham
VSG
Days
50
#
Gra
ms **
Body Weight Change after VSG
Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
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Results: serum bile acid levels
Four Weeks Bile Acid Levels
HFD Naï
ve
SPF
Sham VSG
0
10
20
30
40**
******
um
ol/L
Serum Bile Acid Levels after VSG
Fasting Bile Acids
Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
14 Days Post Surgery
-16-14-12-10-80
20
40
60
80
Weight Loss/Gain (g)
Bile
Ac
id C
on
ce
ntr
ati
on
(u
mo
l/L)
HFD Naï
ve
Sham
Sham-P
FVSG
0 .0
0 .5
1 .0
1 .5
2 .0
2 .5
******
**
Ta
uro
urs
od
eo
xy
ch
olic
ac
id
(lo
g t
ran
sfo
rma
tio
n)
After VSGTUDCA is higher again!
Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
So why not just give TUDCA or GUDCA?
Bile Acid Diarrhea!
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Bile Acid‐FXR Pathway
Modified from Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
0. 1 2 3 4 5 6 7 8 10 12 13 1420
30
40
50WT-Sham
* **** ***
WT-VSG
C
*********
***************
Weeks
Bo
dy
we
ight
(g)
0 1 2 3 4 5 6 7 8 10 12 13 1420
25
30
35
40
KO-shamKO-VSG
D
**
*
Weeks
Bo
dy
we
ight
(g)
Modified from Ryan, Kohli, Seeley et al Nature, May 8, 2014
1 2 3 4 5 6 7 80
1
2
3
WT-shamWT-VSG
***
*****
A
Weeks
HF
D in
take
g/d
1 2 3 4 5 6 7 80
1
2
3
KO-shamKO-VSG
**
*
B
Weeks
HF
D in
take
g/d
Modified from Ryan, Kohli, Seeley et al Nature, May 8, 2014
Fxr ko mice can eat througha smaller stomach!
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So is that it?
Is FXR the answer?
NASH Therapeutics
Lifestyle Rx/Sx Lifestyle
Obeticholic acid (OCA) improved the histological features of NASH in adults
but
Decreased HDLIncreased LDL
NO Pediatric Data on OCA in NASH
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FXR SHP
Bile Acid Synthesis
FGF15
Lipogenesis
ASBT
FXR
Serum Bile Acids
Liver VSG
Ileum
Uhhh… not so fast …
Changes in microbiota
TGR5
WT-s
ham
WT-v
sg
KO-s
ham
KO-v
sg
0.000
0.005
0.010
0.015
***
E
Re
lativ
e a
bun
dan
ceR
ose
bu
ria
0.000 0.005 0.010120
140
160
180
200R2 = 0.75p< 0.05
G
Abundance Roseburia
Blo
od
glu
cose
(m
g/d
L)
Microbiome has an influence
Modified from Ryan, Kohli, Seeley et al Nature, May 8, 2014
Bile Acid‐FXR‐SHP Pathway
Modified from Myronovych, Kohli et al Obesity 2014; 22 (2) 390-400.
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VSG Works in SHP KO Mice
Body Weight Change
0 7 14 21 28 35 42 49 56 60-40
-20
0
20
40
SHP KO VSG
WT VSGSHP KO Sham
WT Sham
***
#
%
*=P<0.05 **=P<0.01 ***=P<0.001
Bile Acids are Elevated VSG in SHP KO mice
4 Weeks Fasting Bile Acids
WT S
ham
WT V
SG
SHP KO S
ham
SHP KO V
SG
0
20
40
60
80
****
Se
rum
bile
ac
id le
ve
ls (
um
ol/L
)
*=P<0.05 **=P<0.01 ***=P<0.001
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NIDDK- K08, R01Ethicon Endo-SurgeryNASPGHAN TakedaProf. Kliewer, UTSWProf. Li Wang, Utah
Questions?