- Email: [email protected]
Effect of Roux-en-Y gastric bypass and sleeve gastrectomy on nonalcoholic fatty liver disease: a comparative study
1 2 3 Surgery for Obesity and Related Diseases ] (2015) 00–00 4 5 6 Original article 7 8 9 10 11 Dvir Froylicha, Ricard Corcellesa,b, Christopher Daiglea, Mena Boulesa, Stacy Brethauera,*, 12 Q3 13 Q1 Philip Schauera a 14 Q4 Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland, Ohio b Fundació Clínic per la Recerca Biomèdica, Hospital Clínic of Barcelona, Universitat de Barcelona, Barcelona, Spain 15 Received January 26, 2015; accepted April 5, 2015 16 17 18 Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the 19 United States; 85%–95% of the morbidly obese population have NAFLD and 33% have non20 alcoholic steatohepatitis. There is a lack of comparative data assessing various bariatric procedures 21 and their effect on NAFLD. 22 Objectives: To assess and compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve 23 gastrectomy (SG) on NAFLD. 24 Setting: Academic Center, United States 25 Methods: All bariatric cases performed at the authors’ institution (an academic center in the United 26 States) between 2005 and 2012 that had both intraoperative and postoperative liver biopsies were 27 included. NAFLD Activity Score (NAS) and fibrosis stages were used to evaluate improvement in 28 liver histology. Results: Fourteen RYGB and 9 SG patients with liver biopsies were identified. The male to female 29 Q5 ratio was 57% and 73%, respectively; P ¼ .2. RYGB patients were older (56.2 ⫾ 8.6 versus 30 46.3 ⫾ 11.7; P o .05), and had lower initial body mass index (BMI) and higher NAS (51.0 ⫾ 13.0 31 kg/m2 versus 72.7 ⫾ 21.0 kg/m2; P o .05) and (4.4 ⫾ 1.7 versus 2.6 ⫾ 1.6; P o .05), respec32 tively. Prevalence of co-morbidities was comparable between groups. After a mean follow-up of 1.5 33 years, weight loss percentage was 32% ⫾ 11.8% and 25% ⫾ 6.8% after RYGB and SG, respec34 Q6 tively (P value not significant). Percen1tage of excess weight loss was higher in RYGB patients 35 (69.8% ⫾ 27% versus 37.2% ⫾ 12.3 .0%; P o .05). NAS after RYGB significantly improved in all 36 morphologic characteristics, whereas only steatosis and total NAS improved after SG. Fibrosis state 37 improved in both groups but to a greater degree after RYGB (2.5 ⫾ 1.3 versus .3 ⫾ .6; P o .05). 38 Conclusions: There were no significant differences in NAS score decrease after RYGB and SG 39 procedures, although the baseline characteristics of the groups differ. This exploratory data supports the idea of conducting a randomized trial to determine the differential effects of SG and RYGB on 40 Q7 NAFLD. (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and 41 Bariatric Surgery. All rights reserved. 42 43 44 Keywords: Bariatric surgery; Nonalcoholic fatty liver disease; NAFLD; NAFLD activity score; NAS 45 46 47 This study has been accepted at the Obesity Week 2014 meeting for 48 poster presentation. The benefits of bariatric surgery are well documented. Co* 49 Correspondence: Stacy A. Brethauer, M.D., Bariatric and Metabolic morbidities, such as type 2 diabetes mellitus, hypertension, 50 Institute, Cleveland Clinic, 9500 Euclid Avenue, M61, Cleveland, OH hyperlipidemia, obstructive sleep apnea, and degenerative 44195. 51 joint disease, are only a fraction of the obesity-associated E-mail: [email protected] 52 53 http://dx.doi.org/10.1016/j.soard.2015.04.004 54 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved. 55
Effect of Roux-en-Y gastric bypass and sleeve gastrectomy on nonalcoholic fatty liver disease: a comparative study
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diseases that improve after bariatric procedures [1]. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States [2,3]. It is regarded as the hepatic manifestation of metabolic syndrome. It has been shown that 85%–95% of the morbidly obese population have some degree of NAFLD and 33% suffer from nonalcoholic steatohepatitis (NASH) [4–6]. NAFLD is a spectrum of liver dysfunction that is initiated with steatosis that can progress to steatohepatitis and later to fibrosis, cirrhosis, and potentially end-stage liver disease and hepatocellular carcinoma [7]. Although several factors can be involved in the development of NASH, insulin resistance and hepatocyte fat accumulation are believed to be the primary causes of NAFLD by impairing the mitochondrial respiratory chain function that results in an imbalance of anti- and pro-inflammatory factors [8–11]. NAFLD has histologic morphologic features similar to steatosis: ballooning, necroinflammation, and fibrosis. Several studies have shown regression of steatosis and steatohepatitis after weight loss procedures [12–18]. Some even report improvement of hepatic fibrosis after bariatric surgery [14,15,18,19]. Of note, bariatric surgery has been performed in carefully selected patients who have progressed to cirrhosis [19]. Currently, the NAFLD activity score (NAS) classification has been used in only a few studies aimed at evaluating NAFLD resolution after bariatric surgery [13,14]. Furthermore, there is a lack of comparative studies assessing the various bariatric approaches and their effect on NAFLD in morbidly obese patients. This study aims to assess and compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on NAS scores. Materials and methods Patient selection All bariatric cases performed at the authors’ institution between 2005 and 2012 (n = 2960) were retrospectively reviewed after approval by the institutional review board. It is a common practice at the authors’ institution to perform a routine liver biopsy for evaluation of NAFLD in every primary bariatric procedure. Only patients with NAFLD who had both intraoperative and postoperative liver biopsies were included in the analysis. Data collection included patient demographic characteristics, alanine transaminase (ALT), international normalized ratio (INR), NAS parameters, fibrosis stage, weight loss outcomes, and co-morbidity resolution assessment. Operative technique Laparoscopic RYGB was performed in the standard fashion, as was previously described. Pouch volume was approximately 15 mL and Roux and biliopancreatic limbs
were 120–150 cm and 50–60 cm, respectively. SG was created over a 36–40French bougie. Histologic evaluation After biopsy, each specimen was processed and stained with hematoxylin, eosin, and trichrome stain using standard laboratory methods. The NAS was used to score the stage of liver disease. The NAS system ranges from 0–8 and evaluates morphologic features like steatosis (range: 0–4), lobular inflammation (range: 0–3), and hepatocyte ballooning (range: 0–2) [20]. Liver fibrosis was assessed semiquantitatively using a 5-grade scale: 0 (none), 1 (perisinusoidal or periportal), 2 (perisinusoidal and periportal), 3 (bridging fibrosis), and 4 (cirrhosis) [21]. Statistical analysis Parametric data are presented as mean (⫾ standard deviation) and analyzed using paired and unpaired Student’s t test for continuous variables and χ2 test for categorical variables. Results Thirty-one patients with liver biopsies taken intraoperatively and at follow-up were identified. Two patients were excluded because of active hepatitis C infection and 4 others were excluded because of autoimmune hepatitis, insufficient tissue biopsy, biliary cirrhosis, and biliary cholangitis at the time of the second biopsy. Of the 25 remaining patients, 14 underwent RYGB and 11 had SG. The cohort had a male to female ratio of 9:16. Patient demographic characteristics (Table 1) differed between the 2 surgical groups with respect to age and mean initial BMI. The mean BMI was also significantly lower in the RYGB group at the second biopsy (P o .05). Preoperatively, ALT levels were significantly higher in patients who underwent RYGB (50 ⫾ 25.8 versus 25.5 ⫾ 10.5; P o .05). Five patients had abnormal ALT levels preoperatively; all 5 underwent RYGB. The 2 groups did not differ in preoperative INR, the number of preoperative co-morbidities, and American Society of Anesthesiologists (ASA) score. NAFLD was noticed in all patients who also had preoperative ultrasound (n ¼ 16). The postoperative biopsy was taken 1.7 ⫾ .7 years and 1.2 ⫾ .6 years after surgery in the RYGB and SG groups, respectively. Type 2 diabetes mellitus remission rates were not different between the groups (P ¼ .1). The absolute weight loss was 48.9 ⫾ 25.6 kg and 49.5 ⫾ 30.6 kg and weight loss percentage was 32% ⫾ 11.8% and 25% ⫾ 6.8% after RYGB and SG, respectively (P 4 .05) (Table 2). A significantly higher percentage excess weight loss (%EWL) was achieved in the RYGB patients compared with SG patients (69.8 ⫾ 27.1 kg versus 37.2 ⫾ 12.3 kg, P o .05). ALT levels after surgery
120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 T1153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 T2171 172 173 174
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175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229
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Table 1 Comparison of baseline patient characteristic Characteristics
Roux-en-Y gastric bypass (n ¼ 14)
Sleeve gastrectomy (n ¼ 11)
Overall (n ¼ 25)
P value
Age, yr Gender, female, n (%) Initial BMI (kg/m2) BMI at biopsy follow-up (kg/m2) Time between surgery and second biopsy (years) Type 2 diabetes mellitus, n (%) Hypertension, n (%) Dyslipidemia, n (%) Number of co-morbidities Preoperative ALT* Preoperative INR* ASA 3, n (%) ASA 4, n (%)
56.2 ⫾ 8.6 8 (57%) 51.0 ⫾ 13.5 34.5 ⫾ 11.3 1.7 ⫾ .7 8 (57%) 12 (85%) 10 (71%) 3.9 50.0 ⫾ 25.8 .96 ⫾ .27 12 (85%) 2 (15%)
46.3 ⫾ 11.7 8 (73%) 72.7 ⫾ 21.1 53.9 ⫾ 12.6 1.2 ⫾ .6 5 (45%) 9 (82%) 4 (36%) 3.6 25.5 ⫾ 10.5 1.06 ⫾ .11 9 (82%) 2 (18%)
51.8 ⫾ 11.0 16 (64%) 60.6 ⫾ 20.1 43.1 ⫾ 15.2 1.5 ⫾ .7 12 (48%) 21 (84%) 14 (80%) 3.8 39.7 ⫾ 23.9 1.01 ⫾ .23 21 (84%) 4 (16%)
.03 .2 o.05 o.05 .1 .8 .8 .08 .2 o.05 .2 .8 .8
Abbreviations: BMI ¼ body mass index; ALT ¼ alanine transaminase; INR ¼ International Normalized Ratio; ASA ¼ American Society of Anesthesiology Score. * Normal range: ALT: 5–50 U/L, INR: .8–1.2.
T3
T4
were still significantly higher among RYGB patients (41.1 ⫾ 30.1 versus 15.5 ⫾ 5.7; P o .05). In patients who underwent RYGB, all of the NAS components showed a significant improvement between the 2 biopsies (Table 3). Among the SG patients, all components showed improvement, but only steatosis was significantly improved. The fibrosis state in both groups showed improvement, although statistical significance was not achieved. Patients who were scheduled for RYGB had a higher initial NAS compared with the SG cohort (Table 4) (4.4 ⫾ 1.7 versus 2.6 ⫾ 1.6; P o .01). RYGB patients achieved higher absolute improvements in both NAS and fibrosis stage compared with SG patients, but the differences were not statistically significant. Discussion In the present study, changes in the liver histology of 14 patients who underwent RYGB were compared with changes in 11 patients who underwent SG. Liver histology was evaluated preoperatively and after significant weight loss was achieved. Significant improvement in or resolution of NAFLD and NASH after RYGB and SG was found.
Furthermore, no patients experienced progression of liver morphology based on NAS and 80% showed substantial liver function improvement (decrease in ALT levels); only 5 patients (20%) had a minimal elevation of ALT during follow-up. It has been reported that NAS Z4 is highly predictive of the presence of NASH and a NAS r3 is highly predictive for its absence [20]. In the present study, a NAS score Z4 was observed in 15 (60%) patients at the time of surgery and resolution of NASH was achieved in 14 (93%) of these patients. Patients with varying stages of fibrosis also showed a significant improvement in fibrosis stage. Of note, there were 3 (12%) patients who had worsening fibrosis stage postoperatively (all after RYGB). Mathurin et al. [16] conducted a long-term prospective evaluation of NAFLD using the NAS system at 1 and 5 years after biliointestinal bypass, gastric bypass, and gastric band surgery in 381 patients. In the study, improvement in steatosis and ballooning occurred mainly within the first year and persisted up to 5 years; however, there was a lack of significant improvement of inflammation, and the fibrosis stage worsened at 5 years after surgery. Patients with worsening fibrosis had higher BMI and NAS at 5 years, with a trend toward increasing insulin resistance. The
Table 2 Clinical results after Roux-en-Y gastric bypass and sleeve gastrectomy Factor
Roux-en-Y gastric bypass
Sleeve gastrectomy
P value
Weight loss, kg Weight loss, % %EWL Type 2 diabetes mellitus remission or improvement, n (%) Hypertension remission or improvement, n (%) ALT at follow-up ALT reduction, mean
48.9 ⫾ 25.6 32 ⫾ 11.8 69.8 ⫾ 27.1 7 (87%) 8 (75%) 41.1 ⫾ 30.1 8.8
49.5 ⫾ 30.5 25 ⫾ 5.6 37.2 ⫾ 12.3 4 (80%) 4 (44%) 15.5 ⫾ 5.7 9
n/s n/s o.05 n/s n/s o.05 n/s
Abbreviations: EWL ¼ excess weight loss; ALT ¼ alanine transaminase.
230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284
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Table 3 Histologic characteristics of the NAS system comparing the findings at the time of surgery and at follow-up after weight loss Histologic characteristic Roux-en-Y gastric bypass Steatosis Lobular inflammation Hepatocyte ballooning Fibrosis stage NAS Sleeve gastrectomy Steatosis Lobular inflammation Hepatocyte ballooning Fibrosis stage NAS Abbreviations: Activity Score.
NAS
¼
Biopsy taken at surgery
Follow-up biopsy
P value
1.9 ⫾ .8 1.3 ⫾ .7 1.1 ⫾ .5 2.5 ⫾ 1.3 4.4 ⫾ 1.7
.5 ⫾ .8 .2 ⫾ .4 .2 ⫾ .4 .3 ⫾ .6 1.4 ⫾ 1.7
o.05 o.05 o.05 o.05 o.05
1.1 ⫾ .6 .7 ⫾ .6 .7 ⫾ .7 1.2 ⫾ 1.4 2.6 ⫾ 1.6
.3 ⫾ .5 .2 ⫾ .4 .2 ⫾ .4 .3 ⫾ .6 .9 ⫾ 1.2
o.05 .07 .11 .07 o.05
NAFLD
(nonalcoholic
steatohepatitis)
results of the Mathurin et al. prospective study are consistent with the present study and others with respect to improvement in steatosis and hepatocyte ballooning. Differences in patient demographic characteristics of the comparative groups could account for observed differences in effect on liver pathology in this study. For instance, patients who underwent RYGB were about 10 years older than patients who had SG. The RYGB group also had a lower mean BMI preoperatively, but both groups had comparable co-morbidities profiles. Patients with more advanced liver pathology based on NAS were more likely to be scheduled for RYGB and also experienced higher % EWL at the follow-up in this analysis. Patients who had SG had a significantly higher baseline BMI. These patients were either selected for primary SG or were scheduled to have the operation as a bridge to RYGB because of significant perioperative risk. There was significant improvement Table 4 NAS changes comparison after Roux-en-Y gastric bypass and sleeve gastrectomy Factor
Roux-en-Y Sleeve Overall P gastric bypass gastrectomy (n ¼ 25) value (n ¼ 14, 56%) (n ¼ 11, 44%)
Steatosis Lobular inflammation Hepatocyte ballooning Initial fibrosis state Initial NAS Final lobular inflammation Final hepatocyte ballooning Final fibrosis stage Fibrosis change NAS change Final NAS Abbreviations: Activity Score.
1.9 ⫾ .8 1.3 ⫾ .7 1.1 ⫾ .5 2.5 ⫾ 1.3 4.4 ⫾ 1.7 .2 ⫾ .4
1.1 ⫾ .6 .7 ⫾ .6 .7 ⫾ .7 1.2 ⫾ 1.4 2.6 ⫾ 1.6 .2 ⫾ .4
1.6 ⫾ .8 1.0 ⫾ .7 .9 ⫾ .6 1.9 ⫾ 1.5 3.6 ⫾ 1.8 .4 ⫾ .5
o.05 o.05 .12 .052 o.05 .07
.2 ⫾ .4
.2 ⫾ .4
.2 ⫾ .5
.47
.3 ⫾ .6 .82 ⫾ 1.5 3⫾2 1.4 ⫾ 1.7
.3 ⫾ .6 .86 ⫾ 1.0 1.7 ⫾ 1.7 .9 ⫾ 1.2
NAS
¼
NAFLD
(nonalcoholic
.7 ⫾ 1.2 .054 .84 ⫾ 1.3 .93 2.6 ⫾ 1.8 .1 1.2 ⫾ 1.5 .39 steatohepatitis)
in all morphologic criteria of NAS in patients who underwent RYGB and in fibrosis state as well. After SG, improvements in all NAS criteria were observed, but only steatosis improvements reached a significant change. Regardless of procedure type, both groups achieved significant total NAS improvement. The exact mechanism by which weight loss surgery contributes to the regression of NAFLD remains unknown. One theory suggests a strong association between NAFLD and insulin resistance. Mitochondrial abnormalities have also been implicated as possible mechanism for NASH [22]. Based on these theories, the insulin resistance improvement achieved by weight loss per se or through other mechanisms may restore liver structure and function. In this study, greater improvement in NAS occurred after RYGB. It remains unclear whether these results are due to greater % EWL seen after RYGB compared with SG or via the specific anatomic and physiologic alterations that result from accelerated delivery of duodenal-bypassed nutrients to the distal bowel. In a recent study by Wree et al. [23], visceral adipose tissue and liver tissue was collected from 93 patients who underwent weight loss surgery and the NAS system was used for pathologic grading. The visceral adipocyte diameter correlated to serum markers of inflammation [24] and to the degree of liver injury assessed by NAS and by transaminase levels. NAS values were independent of BMI; however, serum levels of triglycerides, apolipoprotein CIII (ApoCIII) and free fatty acids (FFA) correlated with NAS severity. Six weeks after surgery, blood samples revealed beneficial changes in serum triglycerides, ApoCIII and FFA levels. Of note, follow-up liver biopsies were not obtained in this study to correlate changes in plasma markers. The NAS is a well-recognized scoring system for NAFLD that has the advantage of categorizing changes in liver histology [20]. However, the diagnosis of definitive steatohepatitis or the absence of steatohepatitis does not always correlate with the indicated threshold values using this system [25]. The retrospective nature of the present study, the low number of patients in each group, and potential selection bias are limitations of this comparative study. In addition, the efficacy of bariatric procedure as treatment for NAFLD cannot be accurately compared because of the absence of a nonsurgical control group (such as intensive weight reduction by diet and exercise). Nevertheless, there are no randomized controlled trials that have compared the NAFLD resolution after surgical and nonsurgical approaches.
340 341 342 343 344 345 346 347 348 349 350 351 352 353 Q9354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 Conclusion 391 Both RYGB and SG are effective at restoring liver 392 function and structure in obese patients with NAFLD. The 393 RYGB approach demonstrated an advantage over SG in 394
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regression of NAFLD in this small cohort. However, SG may be an appropriate option for high-risk NAFLD patients because of the lower risk profile compared with RYGB. This issue requires further study, and a randomized trial is needed to determine the most effective strategy in treating NAFLD. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. References [1] Schauer PR, Ikramuddin S, Gourash W, Ramanathan R, Luketich J. Outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg 2000;232(4):515–29. [2] Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122(6):1649–57. [3] Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98(5):960–7. [4] Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121(1):91–100. [5] Crespo J, Fernández-Gil P, Hernández-Guerra M, et al. Are there predictive factors of severe liver fibrosis in morbidly obese patients with non-alcoholic steatohepatitis? Obes Surg 2001;11(3):254–7 [6] Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing roux-en-Y gastric bypass surgery. Obes Surg 2002;12(1):49–51. [7] Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51(5):1820–32. [8] Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24 (1):3–20. [9] Pessayre D, Berson A, Fromenty B, Mansouri A. Mitochondria in steatohepatitis. Semin Liver Dis 2001;21(1):57–69. [10] Day CP, Saksena S. Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 2002;17(Suppl 3):S377–84. [11] Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002;16(5):663–78.
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[12] Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res 2005;13(7):1180–6. [13] de Almeida SR, Rocha PR, Sanches MD, et al. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg 2006;16(3):270–8. [14] Tai CM, Huang CK, Hwang JC, et al. Improvement of nonalcoholic fatty liver disease after bariatric surgery in morbidly obese chinese patients. Obes Surg 2012;22(7):1016–21. [15] Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg 2005;242(4):610–617; discussion 618–20. [16] Mathurin P, Hollebecque A, Arnalsteen L, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137(2):532–40. [17] Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6 (12):1396–402. [18] Moretto M, Kupski C, da Silva VD, Padoin AV, Mottin CC. Effect of bariatric surgery on liver fibrosis. Obes Surg 2012;22(7):1044–9. [19] Shimizu H, Phuong V, Maia M, et al. Bariatric surgery in patients with liver cirrhosis. Surg Obes Relat Dis 2013;9(1):1–6. [20] Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41(6):1313–21. [21] Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94 (9):2467–74. [22] Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001;120(5):1183–92. [23] Wree A, Schlattjan M, Bechmann LP, et al. Adipocyte cell size, free fatty acids and apolipoproteins are associated with non-alcoholic liver injury progression in severely obese patients. Metabolism 2014;63 (12):1542–52. [24] Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42 (5):987–1000. [25] Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53 (3):810–20.
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diseases that improve after bariatric procedures [1]. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States [2,3]. It is regarded as the hepatic manifestation of metabolic syndrome. It has been shown that 85%–95% of the morbidly obese population have some degree of NAFLD and 33% suffer from nonalcoholic steatohepatitis (NASH) [4–6]. NAFLD is a spectrum of liver dysfunction that is initiated with steatosis that can progress to steatohepatitis and later to fibrosis, cirrhosis, and potentially end-stage liver disease and hepatocellular carcinoma [7]. Although several factors can be involved in the development of NASH, insulin resistance and hepatocyte fat accumulation are believed to be the primary causes of NAFLD by impairing the mitochondrial respiratory chain function that results in an imbalance of anti- and pro-inflammatory factors [8–11]. NAFLD has histologic morphologic features similar to steatosis: ballooning, necroinflammation, and fibrosis. Several studies have shown regression of steatosis and steatohepatitis after weight loss procedures [12–18]. Some even report improvement of hepatic fibrosis after bariatric surgery [14,15,18,19]. Of note, bariatric surgery has been performed in carefully selected patients who have progressed to cirrhosis [19]. Currently, the NAFLD activity score (NAS) classification has been used in only a few studies aimed at evaluating NAFLD resolution after bariatric surgery [13,14]. Furthermore, there is a lack of comparative studies assessing the various bariatric approaches and their effect on NAFLD in morbidly obese patients. This study aims to assess and compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on NAS scores. Materials and methods Patient selection All bariatric cases performed at the authors’ institution between 2005 and 2012 (n = 2960) were retrospectively reviewed after approval by the institutional review board. It is a common practice at the authors’ institution to perform a routine liver biopsy for evaluation of NAFLD in every primary bariatric procedure. Only patients with NAFLD who had both intraoperative and postoperative liver biopsies were included in the analysis. Data collection included patient demographic characteristics, alanine transaminase (ALT), international normalized ratio (INR), NAS parameters, fibrosis stage, weight loss outcomes, and co-morbidity resolution assessment. Operative technique Laparoscopic RYGB was performed in the standard fashion, as was previously described. Pouch volume was approximately 15 mL and Roux and biliopancreatic limbs
were 120–150 cm and 50–60 cm, respectively. SG was created over a 36–40French bougie. Histologic evaluation After biopsy, each specimen was processed and stained with hematoxylin, eosin, and trichrome stain using standard laboratory methods. The NAS was used to score the stage of liver disease. The NAS system ranges from 0–8 and evaluates morphologic features like steatosis (range: 0–4), lobular inflammation (range: 0–3), and hepatocyte ballooning (range: 0–2) [20]. Liver fibrosis was assessed semiquantitatively using a 5-grade scale: 0 (none), 1 (perisinusoidal or periportal), 2 (perisinusoidal and periportal), 3 (bridging fibrosis), and 4 (cirrhosis) [21]. Statistical analysis Parametric data are presented as mean (⫾ standard deviation) and analyzed using paired and unpaired Student’s t test for continuous variables and χ2 test for categorical variables. Results Thirty-one patients with liver biopsies taken intraoperatively and at follow-up were identified. Two patients were excluded because of active hepatitis C infection and 4 others were excluded because of autoimmune hepatitis, insufficient tissue biopsy, biliary cirrhosis, and biliary cholangitis at the time of the second biopsy. Of the 25 remaining patients, 14 underwent RYGB and 11 had SG. The cohort had a male to female ratio of 9:16. Patient demographic characteristics (Table 1) differed between the 2 surgical groups with respect to age and mean initial BMI. The mean BMI was also significantly lower in the RYGB group at the second biopsy (P o .05). Preoperatively, ALT levels were significantly higher in patients who underwent RYGB (50 ⫾ 25.8 versus 25.5 ⫾ 10.5; P o .05). Five patients had abnormal ALT levels preoperatively; all 5 underwent RYGB. The 2 groups did not differ in preoperative INR, the number of preoperative co-morbidities, and American Society of Anesthesiologists (ASA) score. NAFLD was noticed in all patients who also had preoperative ultrasound (n ¼ 16). The postoperative biopsy was taken 1.7 ⫾ .7 years and 1.2 ⫾ .6 years after surgery in the RYGB and SG groups, respectively. Type 2 diabetes mellitus remission rates were not different between the groups (P ¼ .1). The absolute weight loss was 48.9 ⫾ 25.6 kg and 49.5 ⫾ 30.6 kg and weight loss percentage was 32% ⫾ 11.8% and 25% ⫾ 6.8% after RYGB and SG, respectively (P 4 .05) (Table 2). A significantly higher percentage excess weight loss (%EWL) was achieved in the RYGB patients compared with SG patients (69.8 ⫾ 27.1 kg versus 37.2 ⫾ 12.3 kg, P o .05). ALT levels after surgery
120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 T1153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 T2171 172 173 174
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Table 1 Comparison of baseline patient characteristic Characteristics
Roux-en-Y gastric bypass (n ¼ 14)
Sleeve gastrectomy (n ¼ 11)
Overall (n ¼ 25)
P value
Age, yr Gender, female, n (%) Initial BMI (kg/m2) BMI at biopsy follow-up (kg/m2) Time between surgery and second biopsy (years) Type 2 diabetes mellitus, n (%) Hypertension, n (%) Dyslipidemia, n (%) Number of co-morbidities Preoperative ALT* Preoperative INR* ASA 3, n (%) ASA 4, n (%)
56.2 ⫾ 8.6 8 (57%) 51.0 ⫾ 13.5 34.5 ⫾ 11.3 1.7 ⫾ .7 8 (57%) 12 (85%) 10 (71%) 3.9 50.0 ⫾ 25.8 .96 ⫾ .27 12 (85%) 2 (15%)
46.3 ⫾ 11.7 8 (73%) 72.7 ⫾ 21.1 53.9 ⫾ 12.6 1.2 ⫾ .6 5 (45%) 9 (82%) 4 (36%) 3.6 25.5 ⫾ 10.5 1.06 ⫾ .11 9 (82%) 2 (18%)
51.8 ⫾ 11.0 16 (64%) 60.6 ⫾ 20.1 43.1 ⫾ 15.2 1.5 ⫾ .7 12 (48%) 21 (84%) 14 (80%) 3.8 39.7 ⫾ 23.9 1.01 ⫾ .23 21 (84%) 4 (16%)
.03 .2 o.05 o.05 .1 .8 .8 .08 .2 o.05 .2 .8 .8
Abbreviations: BMI ¼ body mass index; ALT ¼ alanine transaminase; INR ¼ International Normalized Ratio; ASA ¼ American Society of Anesthesiology Score. * Normal range: ALT: 5–50 U/L, INR: .8–1.2.
T3
T4
were still significantly higher among RYGB patients (41.1 ⫾ 30.1 versus 15.5 ⫾ 5.7; P o .05). In patients who underwent RYGB, all of the NAS components showed a significant improvement between the 2 biopsies (Table 3). Among the SG patients, all components showed improvement, but only steatosis was significantly improved. The fibrosis state in both groups showed improvement, although statistical significance was not achieved. Patients who were scheduled for RYGB had a higher initial NAS compared with the SG cohort (Table 4) (4.4 ⫾ 1.7 versus 2.6 ⫾ 1.6; P o .01). RYGB patients achieved higher absolute improvements in both NAS and fibrosis stage compared with SG patients, but the differences were not statistically significant. Discussion In the present study, changes in the liver histology of 14 patients who underwent RYGB were compared with changes in 11 patients who underwent SG. Liver histology was evaluated preoperatively and after significant weight loss was achieved. Significant improvement in or resolution of NAFLD and NASH after RYGB and SG was found.
Furthermore, no patients experienced progression of liver morphology based on NAS and 80% showed substantial liver function improvement (decrease in ALT levels); only 5 patients (20%) had a minimal elevation of ALT during follow-up. It has been reported that NAS Z4 is highly predictive of the presence of NASH and a NAS r3 is highly predictive for its absence [20]. In the present study, a NAS score Z4 was observed in 15 (60%) patients at the time of surgery and resolution of NASH was achieved in 14 (93%) of these patients. Patients with varying stages of fibrosis also showed a significant improvement in fibrosis stage. Of note, there were 3 (12%) patients who had worsening fibrosis stage postoperatively (all after RYGB). Mathurin et al. [16] conducted a long-term prospective evaluation of NAFLD using the NAS system at 1 and 5 years after biliointestinal bypass, gastric bypass, and gastric band surgery in 381 patients. In the study, improvement in steatosis and ballooning occurred mainly within the first year and persisted up to 5 years; however, there was a lack of significant improvement of inflammation, and the fibrosis stage worsened at 5 years after surgery. Patients with worsening fibrosis had higher BMI and NAS at 5 years, with a trend toward increasing insulin resistance. The
Table 2 Clinical results after Roux-en-Y gastric bypass and sleeve gastrectomy Factor
Roux-en-Y gastric bypass
Sleeve gastrectomy
P value
Weight loss, kg Weight loss, % %EWL Type 2 diabetes mellitus remission or improvement, n (%) Hypertension remission or improvement, n (%) ALT at follow-up ALT reduction, mean
48.9 ⫾ 25.6 32 ⫾ 11.8 69.8 ⫾ 27.1 7 (87%) 8 (75%) 41.1 ⫾ 30.1 8.8
49.5 ⫾ 30.5 25 ⫾ 5.6 37.2 ⫾ 12.3 4 (80%) 4 (44%) 15.5 ⫾ 5.7 9
n/s n/s o.05 n/s n/s o.05 n/s
Abbreviations: EWL ¼ excess weight loss; ALT ¼ alanine transaminase.
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Table 3 Histologic characteristics of the NAS system comparing the findings at the time of surgery and at follow-up after weight loss Histologic characteristic Roux-en-Y gastric bypass Steatosis Lobular inflammation Hepatocyte ballooning Fibrosis stage NAS Sleeve gastrectomy Steatosis Lobular inflammation Hepatocyte ballooning Fibrosis stage NAS Abbreviations: Activity Score.
NAS
¼
Biopsy taken at surgery
Follow-up biopsy
P value
1.9 ⫾ .8 1.3 ⫾ .7 1.1 ⫾ .5 2.5 ⫾ 1.3 4.4 ⫾ 1.7
.5 ⫾ .8 .2 ⫾ .4 .2 ⫾ .4 .3 ⫾ .6 1.4 ⫾ 1.7
o.05 o.05 o.05 o.05 o.05
1.1 ⫾ .6 .7 ⫾ .6 .7 ⫾ .7 1.2 ⫾ 1.4 2.6 ⫾ 1.6
.3 ⫾ .5 .2 ⫾ .4 .2 ⫾ .4 .3 ⫾ .6 .9 ⫾ 1.2
o.05 .07 .11 .07 o.05
NAFLD
(nonalcoholic
steatohepatitis)
results of the Mathurin et al. prospective study are consistent with the present study and others with respect to improvement in steatosis and hepatocyte ballooning. Differences in patient demographic characteristics of the comparative groups could account for observed differences in effect on liver pathology in this study. For instance, patients who underwent RYGB were about 10 years older than patients who had SG. The RYGB group also had a lower mean BMI preoperatively, but both groups had comparable co-morbidities profiles. Patients with more advanced liver pathology based on NAS were more likely to be scheduled for RYGB and also experienced higher % EWL at the follow-up in this analysis. Patients who had SG had a significantly higher baseline BMI. These patients were either selected for primary SG or were scheduled to have the operation as a bridge to RYGB because of significant perioperative risk. There was significant improvement Table 4 NAS changes comparison after Roux-en-Y gastric bypass and sleeve gastrectomy Factor
Roux-en-Y Sleeve Overall P gastric bypass gastrectomy (n ¼ 25) value (n ¼ 14, 56%) (n ¼ 11, 44%)
Steatosis Lobular inflammation Hepatocyte ballooning Initial fibrosis state Initial NAS Final lobular inflammation Final hepatocyte ballooning Final fibrosis stage Fibrosis change NAS change Final NAS Abbreviations: Activity Score.
1.9 ⫾ .8 1.3 ⫾ .7 1.1 ⫾ .5 2.5 ⫾ 1.3 4.4 ⫾ 1.7 .2 ⫾ .4
1.1 ⫾ .6 .7 ⫾ .6 .7 ⫾ .7 1.2 ⫾ 1.4 2.6 ⫾ 1.6 .2 ⫾ .4
1.6 ⫾ .8 1.0 ⫾ .7 .9 ⫾ .6 1.9 ⫾ 1.5 3.6 ⫾ 1.8 .4 ⫾ .5
o.05 o.05 .12 .052 o.05 .07
.2 ⫾ .4
.2 ⫾ .4
.2 ⫾ .5
.47
.3 ⫾ .6 .82 ⫾ 1.5 3⫾2 1.4 ⫾ 1.7
.3 ⫾ .6 .86 ⫾ 1.0 1.7 ⫾ 1.7 .9 ⫾ 1.2
NAS
¼
NAFLD
(nonalcoholic
.7 ⫾ 1.2 .054 .84 ⫾ 1.3 .93 2.6 ⫾ 1.8 .1 1.2 ⫾ 1.5 .39 steatohepatitis)
in all morphologic criteria of NAS in patients who underwent RYGB and in fibrosis state as well. After SG, improvements in all NAS criteria were observed, but only steatosis improvements reached a significant change. Regardless of procedure type, both groups achieved significant total NAS improvement. The exact mechanism by which weight loss surgery contributes to the regression of NAFLD remains unknown. One theory suggests a strong association between NAFLD and insulin resistance. Mitochondrial abnormalities have also been implicated as possible mechanism for NASH [22]. Based on these theories, the insulin resistance improvement achieved by weight loss per se or through other mechanisms may restore liver structure and function. In this study, greater improvement in NAS occurred after RYGB. It remains unclear whether these results are due to greater % EWL seen after RYGB compared with SG or via the specific anatomic and physiologic alterations that result from accelerated delivery of duodenal-bypassed nutrients to the distal bowel. In a recent study by Wree et al. [23], visceral adipose tissue and liver tissue was collected from 93 patients who underwent weight loss surgery and the NAS system was used for pathologic grading. The visceral adipocyte diameter correlated to serum markers of inflammation [24] and to the degree of liver injury assessed by NAS and by transaminase levels. NAS values were independent of BMI; however, serum levels of triglycerides, apolipoprotein CIII (ApoCIII) and free fatty acids (FFA) correlated with NAS severity. Six weeks after surgery, blood samples revealed beneficial changes in serum triglycerides, ApoCIII and FFA levels. Of note, follow-up liver biopsies were not obtained in this study to correlate changes in plasma markers. The NAS is a well-recognized scoring system for NAFLD that has the advantage of categorizing changes in liver histology [20]. However, the diagnosis of definitive steatohepatitis or the absence of steatohepatitis does not always correlate with the indicated threshold values using this system [25]. The retrospective nature of the present study, the low number of patients in each group, and potential selection bias are limitations of this comparative study. In addition, the efficacy of bariatric procedure as treatment for NAFLD cannot be accurately compared because of the absence of a nonsurgical control group (such as intensive weight reduction by diet and exercise). Nevertheless, there are no randomized controlled trials that have compared the NAFLD resolution after surgical and nonsurgical approaches.
340 341 342 343 344 345 346 347 348 349 350 351 352 353 Q9354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 Conclusion 391 Both RYGB and SG are effective at restoring liver 392 function and structure in obese patients with NAFLD. The 393 RYGB approach demonstrated an advantage over SG in 394
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regression of NAFLD in this small cohort. However, SG may be an appropriate option for high-risk NAFLD patients because of the lower risk profile compared with RYGB. This issue requires further study, and a randomized trial is needed to determine the most effective strategy in treating NAFLD. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. References [1] Schauer PR, Ikramuddin S, Gourash W, Ramanathan R, Luketich J. Outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg 2000;232(4):515–29. [2] Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122(6):1649–57. [3] Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98(5):960–7. [4] Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121(1):91–100. [5] Crespo J, Fernández-Gil P, Hernández-Guerra M, et al. Are there predictive factors of severe liver fibrosis in morbidly obese patients with non-alcoholic steatohepatitis? Obes Surg 2001;11(3):254–7 [6] Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing roux-en-Y gastric bypass surgery. Obes Surg 2002;12(1):49–51. [7] Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51(5):1820–32. [8] Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24 (1):3–20. [9] Pessayre D, Berson A, Fromenty B, Mansouri A. Mitochondria in steatohepatitis. Semin Liver Dis 2001;21(1):57–69. [10] Day CP, Saksena S. Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 2002;17(Suppl 3):S377–84. [11] Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002;16(5):663–78.
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