STOPNASH R Kohli new - NASPGHAN · composition? 9 Area Under the Curve Altered Enterohepatic Circulation? 10 0 500 1000 1500 2000 Taurine Glycine IT * Sham PF Serum Conjugated Bile

1

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)

2

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

3

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

4

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

6

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.

8

Fasting serum bile acid

Sham BD

0

20

40

60**

Bile

Ac

id(

M /

L)

Bile Diversion


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?

9

Area Under the Curve

Altered Enterohepatic Circulation

?

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


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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.

12

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


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!


So why not just give TUDCA or GUDCA?

Bile Acid Diarrhea!

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Bile Acid‐FXR Pathway


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


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


Bile Acid‐FXR‐SHP Pathway


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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?

Documents

STOPNASH R Kohli new - NASPGHAN · composition? 9 Area Under the Curve Altered Enterohepatic Circulation? 10 0 500 1000 1500 2000 Taurine Glycine IT * Sham PF Serum Conjugated Bile