1. Philippe Mathurin, Antoine Hollebecque, Laurent Arnalsteen§,, David Buob¶, Emmanuelle Leteurtre¶, Robert Caiazzo§,, Marie Pigeyre#, Hélène Verkindt, Sébastien Dharancy, ‡, Alexandre Louvet, ‡, Monique Romon# and François Pattou§, CHRU de Lille, Université Lille 2, France Gastroenterology 2009; 137: 532-540

2.  Severe obesity  Liver injury (2 hit hypothesis)  NAFLD  Bariatric surgery  Wt. loss, decreased CVD, increased survival  Long term effects? ▪on liver injury (fibrosis?)  Insulin resistance  Related to CVD risk and obesity-induced liver injury

3.  Bariatric surgery  Long-term effects on obesity-induced liver injury ▪One and five year evolution of fibrosis and histologic features of NAFLD Liver injury Obesity Bariatric surgery

4.  Between 1994 and December 2005  381 patients  Biliointestinal bypass, gastric bypass, and gastric band surgery  Biliointestinal bypass ▪jejunoileostomy coupled with cholecystojejunal anastomosis.  Gastric band ▪an adjustable gastric band inserted by laparoscopy  Gastric bypass ▪a Roux en-Y gastric bypass consisting of partitioning of the upper stomach to create a small gastric pouch and gastrojejunostomy to reestablish gastrointestinal continuity

5.  Before and 1 and 5 years after surgery:  weight, BMI, blood pressure, alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), prothrombin time, platelets, serum triglyceride, cholesterolemia, fasting blood glucose, and fasting insulin. Diabetes, hypercholesterolemia, and hypertriglyceridemia were defined as follows: fasting blood glucose > 1.26 g/L, cholesterolemia > 2.4 g/L, and serum triglyceride > 1.5 g/L.  Insulin resistance (IR)  the quantitative insulin sensitivity check index (QUICKI)  QUICKI = 1/[(log fasting insulin) + (log fasting plasma glucose)]  The IR index is equal to 1/QUICKI  “refractory IR profile,” ▪defined by an insulin resistance index at 1 year which was >3.13

6.  Histologic study (two pathologists)  Liver biopsy (baseline, 1 and 5 years)  NAS (NAFLD score) ▪Steatosis 0-3 ▪Inflammation 0-3 ▪Ballooning 0-2  NASH ▪Probable ≥ NAS 3 ▪Definite ≥ NAS 5  Liver fibrosis ▪F0-F4

9.  Steatosis  IR index (OR, 7.5; 95% CI, 2.5-22.2; p=0.0003)  ALT (OR, 1.04; 95% CI, 1.0007-1.07; p=0.002)  Ballooning  IR index (OR, 4.3; 95% CI, 1.33-13.8; p=0.02)  ALT (OR, 1.02; 95% CI, 1.005-1.04; p=0.01)  Age (OR, 1.03; 95% CI, 1.03-1.1; p=0.002)  Inflammation  IR index (OR, 5.5; 95% CI, 1.75-17.3; p=0.0004)  ALT (OR, 1.02; 95% CI, 1.0-1.03; p=0.05)  Age (OR, 1.06; 95% CI, 1.02-1.1; p=0.03)

12.  19.8% of patients showed fibrosis progression at 5 years  Higher BMI, NAS, steatosis, ballooning, inflammation, fibrosis, IR  BMI loss was not associated with fibrosis evolution (-18% vs -20.7%; p=0.19)

15.  Steatosis  BMI loss at 1 year ▪Did not predict persistence of steatosis at 5 years ▪-19.4% vs. -20.6% (p=0.47)  Inflammation  No change  Ballooning  GGT, ALT, TG, IR index, steatosis score  Not BMI

16.  1 year  Higher steatosis score, NAS, inflammation, ballooning  5 year  Persistent steatosis (68% vs 31%, p<0.0001)  Higher NAS (1.64 vs 0.81, p<0.0003)  Inflammation (0.49 vs 0.17; p=0.01)  Ballooning (0.3 vs 0.05; p=0.03)

17.  Persistent steatosis at 5 years  Baseline steatosis (OR, 1.03, p=0.001)  Refractory IR (OR, 5.36;p=0.001)  Ballooning at 5 years  Baseline ALT (OR, 1.02, p=0.05)  Baseline ballooning (OR, 3.8; p=0.007)  Refractory IR ( OR, 6; p=0.007)

19.  Fibrosis worsened at 5 years  Although 95% of patients had a fibrosis score F1 at 5 years  Improvement in steatosis and ballooning occurred  mainly within the first year and persisted up to 5 years;  The mechanisms of pathogenesis of steatosis and ballooning were closely linked to IR  their long-term evolution may be predicted by early improvement in IR.

20.  The first prospective evidence  NAFLD after bariatric surgery  IR > weight loss (BMI) Liver injury Obesity Bariatric surgery IR