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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
5
6
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
8
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
12
Glucose production
lipolysis
Insulin Resistance
Glucose uptake
FFA
FFA
Insulin Resistance is a Multisystem Disorder
13
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
15
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)
16
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
17
ββββ−−−−oxidation
FFA
TG
VLDL
FFA
Insulin resistance
lipolysis
ROS
18
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)
*
Riduzione eccesso di peso
** *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)
*
Riduzione eccesso di peso
* **69
2865 27
52 2217 5 2
γγγγGT vn <28U/l
19
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
paz paz 1616mesi mesi 2424
paz paz 3636mesi mesi 2626
paz paz 1919mesi mesi 2121
paz paz 5151mesi mesi 1818
paz paz 7070mesi mesi 1515
paz paz 1616mesi mesi 1010
De Ridder RJJ et al Aliment Pharmacol Ther 2007
20
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)
paz paz 6969mesi mesi 2727
paz paz 1616mesi mesi 2424
paz paz 3636mesi mesi 2626
paz paz 1919mesi mesi 2121
paz paz 5151mesi mesi 1818
paz paz 104104mesi mesi 4141
paz paz 1616mesi mesi 1010
paz paz 7070mesi mesi 1515
De Ridder RJJ et al Aliment Pharmacol Ther 2007
%
21
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 2424paz paz 3636
mesi mesi 2626paz paz 1919
mesi mesi 2121paz paz 5151
mesi mesi 1818paz paz 7070
mesi mesi 1515paz paz 1616
mesi mesi 1010
De Ridder RJJ et al Aliment Pharmacol Ther 2007
%
22
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
23
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.
Mathurin et al Gastroenterology 2009
26
Distribuzione del grado di fibrosi a 5 aa dalla chi rurgia
Mathurin et al Gastroenterology 2009
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
focal pericellular in zone 3F1
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
Mathurin et al Gastroenterology 2009
00000F3 bas 0
02222F2 bas 8
0011117F1 bas 29
10341121F0 bas 166
F4 5aaF3 5aaF2 5aaF1 5aaF0 5aa
cirrhosisF4
Bridging or extensive fibrosis with architectural distortion
F3
Perivenular pericellular in zone 2-3
F2
focal pericellular in zone 3F1
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
Distribuzione del grado di fibrosi a 5 aa dalla chirurgia
Mathurin et al Gastroenterology 2009
00000F3 bas 0
02222F2 bas 8
0011117F1 bas 29
10341121F0 bas 166
F4 5aaF3 5aaF2 5aaF1 5aaF0 5aa
cirrhosisF4
Bridging or extensive fibrosis with architectural distortion
F3
Perivenular pericellular in zone 2-3
F2
focal pericellular in zone 3F1
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
Distribuzione del grado di fibrosi a 5 aa dalla chirurgia
Mathurin et al Gastroenterology 2009
00000F3 bas 0
02222F2 bas 8
0011117F1 bas 29
10341121F0 bas 166
F4 5aaF3 5aaF2 5aaF1 5aaF0 5aa
cirrhosisF4
Bridging or extensive fibrosis with architectural distortion
F3
Perivenular pericellular in zone 2-3
F2
focal pericellular in zone 3F1
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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