Effetti metabolici della chirurgia bariatrica

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1 University of Pisa 1 th A.I.S.F. PRE-MEETING COURSE Liver Disease, Life Style and Behaviour School of Medicine Effetti metabolici della chirurgia bariatrica Stefania Camastra Dipartimento di Medicina Interna Università of Pisa 1

2 Indicazioni alla Chirurgia Bariatrica Pazienti con BMI > 4 kg/m Pazienti con BMI tra 35 e 4 kg/m in presenza di comorbilità ( diabete tipo, patologie cardiorespiratorie, gravi malattie articolari, ecc.) Linee Guida SICOB 8

3 Adjustable gastric band Restrictive procedures Sleeve gastrectomy Restrictive and malabsorptive procedure LAGB VBG Roux-en-Y gastric bypass Vertical banded gastroplasty Malabsorptive procedures Biliopancreatic diversion BPD cc Gastrojejunal anastomosis between 3-75 cm from Treitz Excluded biliary limb 3 cc Alimentary limb Excluded biliary limb 5 cm Alimentary limb Entero-enteroanastomosis at 75-1 cm distal to the gastrojejunal anastomosis Entero-enteroanastomosis at 5 cm proximal to the ileocecal valve 3

4 Effect of bariatric surgery on weight loss and comorbidities WEIGHT REDUCTION Meta-analysis: 136 studies (94) patients published between 199 and 3 Buchwald H. et al. JAMA. 4. 9: Gastric banding Gastric Bypass BPD restrictive restrictive-malabsorptive malabsorptive TOT Absolute weight loss (kg) Excess weight loss (%) HYPERTENSION Resolved (%) Resolved or improved (%) Obstructive Sleep Apnea Resolved (%) Resolved or improved (%) HYPERLIPIDEMIA Hypercholester. Improved (%) Hypertriglycerid. Improved (%) DIABETES COURSE (*) Resolved overall (%) Resolved < years (%) Resolved > years (%) (*) Buchwald H. et al. Am J Med. 9 Meta-analysis: 61 studies published between 199 and 6 4

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6 Effect of BPD on insulin secretion Insulin secretion rate (pmol/min) a.m. 1 a.m. p.m. 6 p.m. 1 p.m. a.m. Time of day Obese pre-surgery (BMI 51 ± 3 kg/m) Obese 6 months post-surgery (BMI 39 ± 3 kg/m) Obese years post-surgery (BMI 33 ± 3 kg/m) shaded green area: means ± SD of the Control group (BMI 6 ± 1 kg/m) Camastra S. et al Diabetes 5;54:38-9 6

7 Massive weight loss by BPD normalizes the ß-cell glucose sensitivity in diabetic subjects 1 Glucose (mmol/l) Insulin secretion rate (pmol/min) a.m. 1 a.m. 4 p.m. 8 p.m. 1 p.m. 4 a.m. 1 Diabetic pre-surgery (BMI 49± 3 kg/m) 1 Diabetic post-surgery (BMI 33 ± 3 kg/m) shaded green area: means ± SD of the Obese non diabetic post-surgery (BMI 33 ± 3 kg/m) Plasma glucose ( mmol /l) Camastra S et al. Diabetes Care 7 7

8 Effect of BPD on insulin sensitivity (follow-up years) p <.5 vs Controls 7 p = ns vs Controls M (µmol/min/kg FFM ) BMI 6.5 BMI 51.1 BMI 33.1 Controls Obese Diabetes adapted from Camastra S et al. Diabetes 5 and Camastra S et al. Diabetes Care 7 BMI 49.5 BMI 33.1 p =.1 vs Obese post BPD pre BPD post BPD Adiponectin (µg/ml) BMI 51.1 p =.1 BMI

9 Massive weight loss determines intramyocellular fat depletion and a proportional improvement of insulin sensitivitity Before weight loss 7 After weight loss by BPD Insulin-sensitivity (µmol/min / kg FFM ) controls obese obese post-diet obese post-bpd 1 r =.49; p< Intramyocellular fat (arbitrary units) adapted from Greco AV et al. Diabetes 51: , 9

10 (pmol/min/m) plasma glucose(mmol/l) Effect of RYGB on beta-cell function Fasting insulin secretion BMI 6.1 Controls Controls p <.5 Diabetic p <.5 BMI 3.6 BMI 49.5 Diabetic p ns vs Controls p <ns vs Controls pre RYGB post RYGB (pmol/min/m/pm) Beta-cell glucose sensitivity BMI 6.1 Controls p <.1 BMI 3.6 BMI 49.5 Diabetic p <.5 vs Controls pre RYGB post RYGB Unpublished personal data 1

11 Effect of RYGB on insulin sensitivity 6 p <.5 1 year post vs Controls M (µmol/min/kg FFM ) BMI 6.1 p <.1 BMI 54.7 BMI 36.1 BMI 49.5 p <.1 BMI 3.6 pre surgery 1year post Controls Obese Diabetic Unpublished personal data 11

12 Insulin Resistance is a Multisystem Disorder Insulin Resistance Glucose production Glucose uptake lipolysis FFA FFA 1

13 Tracer study Euglycaemic hyperinsulinaemic clamp (4 mu/m /min) combined with infusion of [6,6- H ]-glucose Hepatic glucose production (HGP) [ H 5 ]-glycerol Lipolysis (glycerol release or RaGLY) Tissue insulin resistance H-IR HGP x fasting plasma insulin M-IS IS Rate of glucose disappearance (M value + HGP) over steady state plasma insulin AT-IR RaGLY x fasting plasma insulin 13

14 M-IS nmol/min/kg FFM /pm 1 Effect of RYGB on tissue insulin sensitivity AT-IR 1,4 mmol/min/kg FM /pm 1, 1,8,6,4, muscle insulin-sensitivity Controls p <.1 p <.1 Obese p <.5 Diabetic adipose tissue insulin-resistance p <.1 p <.1 p <.5 H-IR mmol/min/kg FFM /pm,4 1,6 1,,8,4 basal Controls weeks post RYGB 1 year post RYGB hepatic insulin-resistance p <.1 p <.5 Obese p <.1 p <.5 Diabetic BMI (kg/m) Controls Obese Diabetic Unpublished personal data 1 Controls Obese Diabetic 14

15 Conclusione La chirurgia bariatrica determina miglioramento o normalizzazione della insulino-resistenza e della funzione β-cellulare La sensibilità all insulina migliora a carico di tutti i tessuti coinvolti nei meccanismi di insulino-resistenza (muscolo, fegato, tessuto adiposo) 15

16 Prevalenza di NAFLD nell obesità grave N Steatosi NASH Fibrosi Cirrosi (%) (%) (%) (%) Luyckx (Int J Ob 1998) Marceau (JCEM 1999) Gholam (Ob Surg ) Padoin (Ob Surg 6) Moretto (Ob Surg 3) Shalhub (Ob Surg 4) Beymer (Arch Surg 3) Dixon (Hepatology 4) Lima (Ob Surg 5) Boza (Ob Surg 5) Stratopoulos (Ob Surg 5) Harnois (Ob Surg 6) De Ridder RJJ et al Aliment Pharmacol Ther 7 16

17 VLDL ROS TG β oxidation FFA FFA lipolysis Insulin resistance 17

18 AST (U/L) ALT (U/L) Effetto della chirurgia bariatrica in pazienti con Steatosi 69 8 * 65 7 Donne Uomini * * * 5 AST vn <19U/l 17 5 Pre-op -5% -5% -75% -1% Riduzione eccesso di peso 69 8 * 65 7 * * * 5 ALT vn <3U/l Pre-op -5% -5% -75% -1% Riduzione eccesso di peso * 17 5 γgt (U/L) Steatosi >3% allõesame istologico Bendaggio gastrico, Gastroplastica, BPD 69 8 * 65 7 * * * 5 Pre-op -5% -5% -75% -1% Riduzione eccesso di peso γgt vn <8U/l 17 5 Wolf AM et al, Ob Surg 5 18

19 Effetto della Chirurgia bariatrica sulla prevalenza di steatosi 1 paz 69 mesi 7 paz 16 mesi 4 paz 36 mesi 6 paz 19 mesi 1 paz 51 mesi 18 paz 16 mesi 1 paz 7 mesi 15 Pre-op Post-op 8 6 % 4 Luyckx (VBG) De Almeida (RYGB) Dixon (LAGB) Barker (RYGB) Stratopoulos (VBG) Clark (RYGB) Mattar (Mixed) De Ridder RJJ et al Aliment Pharmacol Ther 7 19

20 Effetto della Chirurgia bariatrica sulla prevalenza di infiammazione 1 paz 69 mesi 7 paz 16 mesi 4 paz 36 mesi 6 paz 19 mesi 1 paz 51 mesi 18 paz 16 mesi 1 paz 14 mesi 41 paz 7 mesi % Luyckx (VBG) De Almeida (RYGB Dixon (LAGB) Barker (RYGB) Stratopoulos (VBG) Clark (RYGB) Kral (BPD) Mattar (Mixed) De Ridder RJJ et al Aliment Pharmacol Ther 7

21 Effetto della Chirurgia bariatrica sulla prevalenza di fibrosi 1 paz 69 mesi 7 paz 16 mesi 4 paz 36 mesi 6 paz 19 mesi 1 paz 51 mesi 18 paz 16 mesi 1 paz 7 mesi 15 Pre-op Post-op 8 6 % 4 Luyckx (VBG) De Almeida (RYGB Dixon (LAGB) Barker (RYGB) Stratopoulos (VBG) Clark (RYGB) Mattar (Mixed) De Ridder RJJ et al Aliment Pharmacol Ther 7 1

22 Effetto della chirurgia bariatrica sulla NAFLD Meta-analisi: 131 studi esaminati pubblicati fino al 7; 15 selezionati per avere numero sufficiente di soggetti e adeguato follow-up istologico; Mummadi et al. Clin. Gastroent Hepatol. 8. 6: Steatosi Steatoepatite Fibrosi Studi presi in esame (n ) (solo agobiopsia) Prevalenza% (n biopsie esaminate) 83,1 (766 biop) 53,9 (555 biop) 65, (11 biop) Risoluzione (%) ND 69,5 ND Miglioramento o risoluzione (%) 91,6 81,3 65,5 Tipo di intervento (n studi/n sogg) Restrittivo (LAGB, SG, VGB) 4 1 Misto (RYGB) Malassorb (BPD) 1 1 Tecniche miste (BLB, RYGB, SG, LAGB) 1 1

23 BASAL 36 liver biopsies 1 year post surgery 67 liver biopsies 5 year post surgery 11 liver biopsies SURGERY Gastric banding Gastric bypass Biliointestinal bypass (%) 56, 1,8 LIVER HISTOLOGY STEATOSIS NASH probable or definite NASH definite NAS =NAFLD score (-8) : unweighted sum of score for steatosis (-3), lobular inflammation (-3), ballooning (-) > 1% fat droplets NAS > 3 NAS > 5 FO F1 F F3 F4 LIVER FIBROSIS normal focal pericellular in zone 3 Perivenular pericellular in zone -3 Bridging or extensive fibrosis with architectural distortion cirrhosis 3

24 Parametri istologici Pre-chirurgia (36) 1 anno (67) 5 anni (11) Amount of steatosis (%) 37 ± 5 15 ± * 16 ± 7 * NAS. ± ± 1.3* 1. ± 1.3* NAS Inflammation.18 ±.41.±.45.3 ±.45 NAS Ballooning. ±.47.1 ±.36*.1 ±.33* Principali parametri clinici Pre-chirurgia 1 anno 5 anni BMI (kg/m ) 5 ± 8 39 ± 8* 38 ± 8* Serum Cholesterol (g/l).4 ± ±.44* 1.89 ±.46* SerumTriglycerides (g/l) 1.67 ±.1 1. ±.76* 1.6 ±.67* ALT (UI/L) 3.1 ± ± 14 *.8 ± 14.1* γgt (UI/L) 39.9 ± ± 7.8* 9. ± 3* Fasting glucose (g/l) 1.18 ± ±.3 *.94 ±.5 * Insulin Resistance Index 3. ±.35 *.84 ±.35 *.83 ±.35 * Mathurin et al Gastroenterology 9 4

25 Evoluzione del profilo istologico a 5 anni IR non refractory IR refractory (>3.13 to 5 yy) p Persistenza di steatosi (%) NAS Infiammazione Ballooning In analisi multivariata IR refractory era un fattore predittivo indipendente di persistenza di steatosi e ballooning. Mathurin et al Gastroenterology 9 5

26 Distribuzione del grado di fibrosi a 5 aa dalla chirurgia N di biopsie Basale 5 anni 8 6 F bas 166 F1 bas 9 F bas 8 F3 bas 1 FO F1 F F3 F4 F 5aa FO F1 F F3 F4 F1 5aa F 5aa 3 1 normal cirrhosis F3 5aa F4 5aa focal pericellular in zone 3 Perivenular pericellular in zone -3 Bridging or extensive fibrosis with architectural distortion 1 Mathurin et al Gastroenterology 9 6

27 Distribuzione del grado di fibrosi a 5 aa dalla chirurgia N di biopsie Basale 5 anni 8 6 F bas 166 F1 bas 9 F bas 8 F3 bas 1 FO F1 F F3 F4 F 5aa F1 5aa % 8% FO F1 F F3 F4 F 5aa 3 1 normal cirrhosis F3 5aa F4 5aa focal pericellular in zone 3 Perivenular pericellular in zone -3 Bridging or extensive fibrosis with architectural distortion 1 % Mathurin et al Gastroenterology 9 7

28 Distribuzione del grado di fibrosi a 5 aa dalla chirurgia >9% Basale 5 anni F 5aa F1 5aa F 5aa F3 5aa F4 5aa F bas 166 F1 bas % N di biopsie FO F1 F F3 F4 F bas 8 F3 bas FO F1 F F3 normal Perivenular pericellular in zone -3 focal pericellular in zone 3 Bridging or extensive fibrosis with architectural distortion F4 cirrhosis Mathurin et al Gastroenterology 9 8

29 Distribuzione del grado di fibrosi a 5 aa dalla chirurgia N di biopsie Basale 5 anni 8 6 F bas 166 F1 bas 9 F bas 8 F3 bas 1 FO F1 F F3 F4 F 5aa F4 F1 5aa % FO F1 F F3 F 5aa 3 1 normal cirrhosis F3 5aa F4 5aa focal pericellular in zone 3 Perivenular pericellular in zone -3 Bridging or extensive fibrosis with architectural distortion 1 Mathurin et al Gastroenterology 9 9

30 % Evoluzione dei 99 pazienti con probabile o definita NASH (NAS>3) Pre-chirurgia 1 anno 5 anni Probable or Definite NASH % (n) 7.4% (99) 1% (3)* 14.% (33) * Extent of steatosis (%) 66 ± 18 9 ± 4* 6 ± 5* NAS 3.7 ±.9.1 ± 1.5* 1.9 ± 1.6* Inflammation.53 ± ± ±.56 Ballooning.63 ± ±.55*.6 ±.48* Extent of fibrosis.71 ± ± ±.79 Basale (n99) 1 anno (n77) 5 anni (n6) FO F1 F F3 3

31 Conclusioni 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 31