effetti metabolici della chirurgia bariatrica - · pdf file1 effetti metabolici della...

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Effetti metabolici Effetti metabolici della chirurgia bariatricadella chirurgia bariatrica

Dipartimento di Medicina InternaDipartimento di Medicina InternaUniversitUniversit àà of Pisaof Pisa

Stefania CamastraStefania Camastra

University of PisaUniversity of Pisa

School of MedicineSchool of Medicine

12th A.I.S.F. PRE-MEETING COURSE

“Liver Disease, Life Style and Behaviour”

2

Indicazioni alla Chirurgia Bariatrica

Linee Guida Linee Guida SICOB 2008SICOB 2008

• Pazienti con BMI > 40 kg/m 2

• Pazienti con BMI tra 35 e 40 kg/m 2 in presenza di comorbilità ( diabete tipo 2, patologie cardiorespiratorie, gravi malattie articolari, ecc.)

3

Restrictive procedures

Malabsorptive procedures

Adjustable gastric band

Roux-en-Y gastric bypass

Biliopancreatic diversion

Gastrojejunal anastomosis between 30-75 cm from

Treitz

LAGB VBG

BPD 200 cc

30 cc

Entero-enteroanastomosis at 75-100 cm distal to the

gastrojejunal anastomosis

Excluded biliary limb

Alimentary limb

Restrictive and malabsorptive procedure

Vertical banded gastroplasty

Entero-enteroanastomosis at 50 cm proximal to the

ileocecal valve

Excluded biliary limb 250 cm

Alimentary limb

Sleeve gastrectomy

4

Effect of bariatric surgery on weight loss and comorbiditiesMeta-analysis: 136 studies (22094) patients published between 1990 and 2003

Buchwald H. et al. JAMA. 2004. 292:1724-38

Gastric bandingGastric banding Gastric BypassGastric Bypass BPDBPD TOTTOTrestrictive restrictive-malabsorptive malabsorptive

WEIGHT REDUCTIONWEIGHT REDUCTION

Absolute weight loss (kg) 28.6 43.5 46.4 39.7

Excess weight loss (%) 47.5 61.6 70.1 61.2

HYPERTENSIONHYPERTENSION

Resolved (%) 43.2 67.5 83.4 61.7

Resolved or improved (%) 70.8 87.2 75.1 78.5

Obstructive Sleep ApneaObstructive Sleep Apnea

Resolved (%) 95 80.4 91.9 85.7

Resolved or improved (%) 68 94.8 71.2 83.6

HYPERLIPIDEMIAHYPERLIPIDEMIA

Hypercholester. Improved (%) 78 95 87 71.3

Hypertriglycerid. Improved (%) 77 91 100 92.4

DIABETES COURSEDIABETES COURSE (*)Resolved overall (%) 56.7 80.3 95.1 78.1

Resolved < 2 years (%) 55 81.6 94.0 80.3

Resolved > 2 years (%) 58.3 70.9 95.9 74.6

(*) Buchwald H. et al. Am J Med. 2009 Meta-analysis: 621 studies published between 1990 and 2006

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Camastra S. et al Diabetes 2005;54:2382-9

Effect of BPD on insulin secretionEffect of BPD on insulin secretion

6 a.m. 10 a.m. 2 p.m. 6 p.m. 10 p.m. 2 a.m.0

100

200

300

400

500

600

700

800

900

Insu

lin s

ecr

etio

n ra

te (

pm

ol/m

in)

Time of day

Obese pre-surgery (BMI 51 ± 3 kg/m2)

Obese 6 months post-surgery (BMI 39 ± 3 kg/m2)

Obese 2 years post-surgery (BMI 33 ± 3 kg/m2)

shaded green area: means ± SD of theControl group (BMI 26 ± 1 kg/m2)

7

4 5 6 7 8 9 10 110

100

200

300

400

500

600

Plasma glucose ( mmol /l)

Insu

lin s

ecre

tion

rate

(pm

ol/m

in)

4

6

8

10

Glu

cose

(mm

ol/l

)

8 a.m. 12 a.m. 4 p.m. 8 p.m. 12 p.m. 4 a.m.

Massive weight loss by BPD normalizes Massive weight loss by BPD normalizes the the ßß--cell glucose cell glucose sensitivity in diabetic subjectssensitivity in diabetic subjects

shaded green area: means ± SD of theObese non diabetic post-surgery (BMI 33 ± 3 kg/m2)

10 Diabetic pre-surgery (BMI 49± 3 kg/m2)

10 Diabetic post-surgery (BMI 33 ± 3 kg/m2)

Camastra S et al. Diabetes Care 2007

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adapted from Camastra S et al. Diabetes 2005and Camastra S et al. Diabetes Care 2007

Effect of BPD on insulin sensitivity (follow-up 2 years)Effect of BPD on insulin sensitivity (follow-up 2 years)

0

10

20

30

40

50

60

70

Controls Obese Diabetes

pre BPD

post BPD

M

(µm

ol/m

in/k

gF

FM

)

BMI33.1

BMI33.1

BMI51.1

BMI49.5

BMI26.5

p <0.05 vs Controls

p = ns vs Controls

p = 0.01 vs Obese post BPD

0

5

10

15

20

BMI51.1

p = 0.01

Adi

pone

ctin

(µ

g/m

l)

BMI33.1

9

(arbitrary units)

controls

obese

obese post-diet

obese post-BPD

0

10

20

30

40

50

60

70

0 0.2 0.4 0.6 0.8 1 1.2 0.4

Intramyocellular fat

r = 0.49; p<0.004

Insu

lin-s

ensi

tivity

(µm

ol/m

in /

kgF

FM

)

Before weight loss

After weight loss by BPD

adapted from Greco AV et al. Diabetes 51: 144-151, 2002

Massive weight loss determines intramyocellular fat depletion and a proportional improvement of insulin

sensitivitity

10

Unpublished personal data

Effect of RYGB on beta-cell functionEffect of RYGB on beta-cell function

0

20

40

60

80

100

Controls Diabetic

pre RYGBpost RYGB

(pm

ol/m

in/m

2/pM

)

BMI32.6BMI

49.5

BMI26.1

p <0.05 vs Controlsp <0.01

Beta-cell glucose sensitivity

0

20

40

60

80

100

120

140

Controls Diabetic

pre RYGBpost RYGB

(pm

ol/m

in/m

2)

BMI32.6BMI

49.5

BMI26.1

p <ns vs Controls

p <0.05

Fasting insulin secretion

0

2

4

6

8

10

Controls Diabetic

p <0.05

p ns vs Controls

pla

sma

gluc

ose(

mm

ol/l)

11

0

10

20

30

40

50

60

Controls Obese Diabetic

pre surgery1year post

M

(µm

ol/m

in/k

gF

FM

)

Effect of RYGB on insulin sensitivityEffect of RYGB on insulin sensitivity

BMI54.7

BMI26.1

BMI36.1 BMI

49.5

BMI32.6

p < 0.05 1 year post vs Controls

p < 0.0001

p < 0.0001

Unpublished personal data

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Glucose production

lipolysis

Insulin Resistance

Glucose uptake

FFA

FFA

Insulin Resistance is a Multisystem Disorder

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Euglycaemic hyperinsulinaemic clamp (40 mU/m2/min)

combined with infusion of

[6,6-2H2]-glucose Hepatic glucose production (HGP)

[2H5]-glycerol Lipolysis (glycerol release or RaGLY)

Tracer studyTracer study

Tissue insulin resistance

ATAT--IRIRRaGLY x fasting plasma insulinHH--IRIR

HGP x fasting plasma insulinMM--ISIS

Rate of glucose disappearance (M value + HGP) over steady state plasma insulin

14

Effect of RYGB on tissue insulin sensitivityEffect of RYGB on tissue insulin sensitivity

2 weeks post RYGB

1 year post RYGB

basal

0

20

40

60

80

100

muscle muscle insulin-sensitivityinsulin-sensitivityM-IS

nmol

/min

/kg

FF

M/p

M

Obese DiabeticControls

p < 0.001 p < 0.001

p < 0.05

0

0,4

0,8

1,2

1,6

2

2,4

mm

ol/m

in/k

g FF

M/p

M

p < 0.001

H-IRhepatic insulin-resistancehepatic insulin-resistance

Obese DiabeticControls

p < 0.001

p < 0.05

p < 0.05

adipose tissue insulin-resistanceadipose tissue insulin-resistance

Obese DiabeticControls0

0,2

0,4

0,6

0,8

1

1,2

1,4AT-IR

mm

ol/m

in/k

gF

M/p

M

p < 0.001

p < 0.001

p < 0.05

10

20

30

40

50

60

BM

I (kg

/m2)

Obese DiabeticControlsUnpublished personal dataUnpublished personal data

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ConclusioneConclusione

• La chirurgia bariatrica determina miglioramento o

normalizzazione della insulino-resistenza e della funzione ββββ-cellulare

• La sensibilità all’insulina migliora a carico di tut ti i tessuti

coinvolti nei meccanismi di insulino-resistenza (muscolo, fegato,

tessuto adiposo)

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N° Steatosi NASH Fibrosi Cirrosi (%) (%) (%) (%)

Luyckx (Int J Ob 1998) 528 74 10 1 0.4

Marceau (JCEM 1999) 82 86 - 74 2

Gholam (Ob Surg 2002) 75 94 80 51 8

Padoin (Ob Surg 2006) 264 91 1.5 - 0.8

Moretto (Ob Surg 2003) 77 83 2.6 - 1.3

Shalhub (Ob Surg 2004) 68 79 35 6 7

Beymer (Arch Surg 2003) 48 85 33 35 0

Dixon (Hepatology 2004) 36 97 67 64 3

Lima (Ob Surg 2005) 112 99 57.7 21 0

Boza (Ob Surg 2005) 127 63 26 26 1.6

Stratopoulos (Ob Surg 2005) 51 98 98 94 0

Harnois (Ob Surg 2006) 92 98 9.8 94 0

Prevalenza di NAFLD nell’obesità grave

De Ridder RJJ et al Aliment Pharmacol Ther 2007

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ββββ−−−−oxidation

FFA

TG

VLDL

FFA

Insulin resistance

lipolysis

ROS

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Effetto della chirurgia bariatrica in pazienti con SteatosiEffetto della chirurgia bariatrica in pazienti con Steatosi

Wolf AM et al, Ob Surg 2005

Steatosi >30% allÕesame istologico

Bendaggio gastrico, Gastroplastica, BPD

0

5

10

15

20

25

Pre-op -25% -50% -75% -100%

Donne Uomini

AS

T (

U/L

) *

Riduzione eccesso di peso

**

*6928

65 2752 22

17 5 2

AST vn <19U/l

0

5

10

15

20

25

30

35

Pre-op -25% -50% -75% -100%

ALT

(U

/L)

*


** *69

2865 27

52 2217 5 2

ALT vn <23U/l

*

0

5

10

15

20

25

30

35

Pre-op -25% -50% -75% -100%

γγ γγGT

(U

/L)

*


* **69

2865 27

52 2217 5 2

γγγγGT vn <28U/l

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Effetto della Chirurgia bariatrica sulla prevalenza diEffetto della Chirurgia bariatrica sulla prevalenza disteatosisteatosi

0

20

40

60

80

100

Luyckx(VBG)

De Almeida(RYGB)

Dixon(LAGB)

Barker(RYGB)

Stratopoulos(VBG)

Clark(RYGB)

Mattar(Mixed)

Pre-opPost-op

%

paz paz 6969mesi mesi 2727








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Effetto della Chirurgia bariatrica sulla prevalenza diEffetto della Chirurgia bariatrica sulla prevalenza diinfiammazioneinfiammazione

0

10

20

30

40

50

60

70

80

90

100

Luyckx (VBG) De Almeida(RYGB

Dixon (LAGB) Barker (RYGB) Stratopoulos(VBG)

Clark (RYGB) Kral (BPD) Mattar (Mixed)










%

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Effetto della Chirurgia bariatrica sulla prevalenza diEffetto della Chirurgia bariatrica sulla prevalenza difibrosifibrosi

0

20

40

60

80

100

Luyckx(VBG)

De Almeida(RYGB

Dixon(LAGB)

Barker(RYGB)

Stratopoulos(VBG)

Clark(RYGB)

Mattar(Mixed)

Pre-opPost-oppaz paz 6969

mesi mesi 2727paz paz 1616






mesi mesi 1010


%

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Effetto della chirurgia bariatrica sulla NAFLD

Meta-analisi: 131 studi esaminati pubblicati fino al 2007; 15 selezionati per avere numero sufficiente di soggetti e adeguato follow-up istologico;

Mummadi et al. Clin. Gastroent Hepatol. 2008. 6:1396-1402

SteatosiSteatosi SteatoepatiteSteatoepatite FibrosiFibrosi

Studi presi in esame (n °°°°) 15 9 5 (solo agobiopsia)

Prevalenza% (n °°°° biopsie esaminate) 83,1 (766 biop) 53,9 (555 biop) 6 5,2 (121 biop)

Risoluzione (%) ND 69,5 ND

Miglioramento o risoluzione (%) 91,6 81,3 65,5

Tipo di intervento (nTipo di intervento (n °°°°°°°° studi/nstudi/n °°°°°°°° sogg)sogg)

Restrittivo (LAGB, SG, VGB) 4 2 1

Misto (RYGB) 8 5 3

Malassorb (BPD) 1 1 0

Tecniche miste (BLB, RYGB, SG, LAGB) 2 1 1

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BASALBASAL362 liver biopsies362 liver biopsies

1 year post surgery1 year post surgery267 liver biopsies267 liver biopsies

5 year post surgery5 year post surgery211 liver biopsies211 liver biopsies

22,82156,2(%)

Biliointestinal bypassGastric bypassGastric bandingSURGERY

LIVER FIBROSIS

cirrhosisF4

Bridging or extensive fibrosis with architectural distortion

F3

Perivenular pericellular in zone 2-3

F2

focal pericellular in zone 3F1

normalFO

NAS > 5NASH definite

NAS > 3NASH probable or definite

> 10% fat droplets

STEATOSIS

NAS =NAFLD score (0-8) : unweighted sum of score f or steatosis (0-3), lobular inflammation (0-3), balloo ning (0-2)

LIVER HISTOLOGY

24

16 ± 27 *15 ± 20 *37 ± 25Amount of steatosis (%)

0.23 ± 0.450.20± 0.450.18 ± 0.41NAS Inflammation

0.1 ± 0.33*0.12 ± 0.36*0.20 ± 0.47NAS Ballooning

1.0 ± 1.3*1.1 ± 1.3*2.0 ± 1.3NAS

5 anni (211)

1 anno (267)

Pre-chirurgia (362)

Parametri istologiciParametri istologici

0.94 ± 0.25 *0.96 ± 0.3 *1.18 ± 0.65Fasting glucose (g/L)

38 ± 8*39 ± 8*50 ± 8BMI (kg/m 2)

2.83 ± 0.35 *2.84 ± 0.35 *3.2 ± 0.35 *Insulin Resistance Index

22.8 ± 14.1*21.4 ± 14 *30.1 ± 21.7ALT (UI/L)

1.89 ± 0.46*1.85 ± 0.44*2.04 ± 0.39Serum Cholesterol (g/L)

29.2 ± 32*30 ± 27.8*39.9 ± 42.4γγγγGT (UI/L)

1.06 ± 0.67*1.2 ± 0.76*1.67 ± 2.1SerumTriglycerides (g/L)

5 anni1 annoPre-chirurgia

Principali parametri cliniciPrincipali parametri clinici

Mathurin et al Gastroenterology 2009

25

0.010.490.17Infiammazione

0.000167.631.1Persistenza di steatosi (%)

0.030.30.05Ballooning

0.00031.640.81NAS

pIR refractory (>3.13 to 5 yy)

IR non refractory

Evoluzione del profilo istologico a 5 anniEvoluzione del profilo istologico a 5 anni

In In analisi multivariata analisi multivariata IR refractory era un IR refractory era un fattore predittivo indipendente di fattore predittivo indipendente di persistenza di steatosi persistenza di steatosi e ballooning.e ballooning.


26

Distribuzione del grado di fibrosi a 5 aa dalla chi rurgia


00000F3 bas0

02222F2 bas8

0011117F1 bas29

10341121F0 bas166

F4 5aaF3 5aaF2 5aaF1 5aaF0 5aa

cirrhosisF4

Bridging or extensive fibrosiswith architectural distortion

F3

Perivenular pericellular inzone 2-3

F2


normalFO

166

140

29

54

8 60 2 0 1

0

20

40

60

80

100

120

140

160

180

FO F1 F2 F3 F4

Basale 5 anni

N� d

i bio

psie

27

Distribuzione del grado di fibrosi a 5 aa dalla chirurgia


00000F3 bas 0

02222F2 bas 8

0011117F1 bas 29

10341121F0 bas 166


cirrhosisF4


F3


F2


normalFO

20%20%

80%80%

166

140

29

54

8 60 2 0 1

0

20

40

60

80

100

120

140

160

180

FO F1 F2 F3 F4

Basale 5 anni

N� d

i bio

psie

28



00000F3 bas 0

02222F2 bas 8

0011117F1 bas 29

10341121F0 bas 166


cirrhosisF4


F3


F2


normalFO

20%20%

>90%>90%

166

140

29

54

8 6 0 2 0 10

20

40

60

80

100

120

140

160

180

FO F1 F2 F3 F4

Basale 5 anni

N� d

i bio

psie

29



00000F3 bas 0

02222F2 bas 8

0011117F1 bas 29

10341121F0 bas 166


cirrhosisF4


F3


F2


normalFO

96%96%

166

140

29

54

8 60 2 0 1

0

20

40

60

80

100

120

140

160

180

FO F1 F2 F3 F4

Basale 5 anni

N°

di b

iops

ie

30

0

10

20

30

40

50

60

FO F1 F2 F3

Basale (n �99)1 anno (n�77)5 anni (n �60)

%

14.2% (33) *12% (32)*27.4% (99)Probable or Definite NASH % (n)

0.66 ± 0.790.76 ± 0.860.71 ± 0.79Extent of fibrosis

0.56 ± 0.560.49 ± 0.640.53 ± 0.55Inflammation

26 ± 25*29 ± 24*66 ± 18Extent of steatosis (%)

0.26 ± 0.48*0.33 ± 0.55*0.63 ± 0.67Ballooning

1.9 ± 1.6*2.1 ± 1.5*3.7 ± 0.9NAS

5 anni1 annoPre-chirurgia

Evoluzione dei 99 pazienti con probabile o definita NASH (NAS>3)

31

ConclusioniConclusioni

•I dati attualmente disponibili indicano un effetto positivo della

chirurgia bariatrica sul quadro istologico della NAFLD per

quel che riguarda il grado di steatosi ed infiammazione che sembra essere legato al miglioramento dell’IR

•Risultati non ancora certi riguardano l’evoluzione della

fibrosi. La maggior parte dei dati attualmente disponibili

sembrano suggerire un miglioramento, ma alcuni studi riportano stabilizzazione o peggioramento sia pure entro i

livelli più bassi

•Studi controllati sono necessari per confermare tali evidenze

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