Bariatric surgery for curing NASH in the morbidly obese?
Authors: Guillaume Lassailly, Robert Caïazzo, François Pattou, Philippe Mathurin
Journal: Journal of Hepatology (2013)

Obesity increases the risk of NAFLD (non-alcoholic fatty liver disease). Bariatric surgery should be considered for severely obese persons with a body mass index (BMI) higher than 40 (or 35 if co-morbidity is present) and who clearly wish to lose weight. It induces long-term weight loss and decreases morbidity, the incidence of cancer, and mortality. Compelling data consistently show a sustained decrease in steatosis, whereas an evolution in ballooning, necro-inflammatory features, and fibrosis remains subject to debate. Bariatric surgery is the most efficient method for losing weight. Malabsorptive procedures (Roux-en-Y gastric bypass (RYGB) or duodenal switch) induce greater weight loss than restrictive procedures (laparoscopic gastric banding (LAGB)), with a range of around 60% of excess weight [[1]Buchwald H. Avidor Y. Braunwald E. Jensen M.D. Pories W. Fahrbach K. et al.Bariatric surgery: a systematic review and meta-analysis.JAMA. 2004; 292: 1724-1737Crossref PubMed Scopus (5302) Google Scholar]. These variations may be due to differing physiological effects. LAGB and sleeve gastrectomy (SG) promote satiation via stretch mechano-receptor activation, with an additional effect after SG related to partial removal of fundus, a secretion site of ghrelin, an orexigenic hormone. Conversely, RYGB acts via several pathways, including early contact of nutrients with the ileum and increased secretion of PYY, an anorectic hormone, and incretins (GLP-1, GLP-2) involved in the enteroinsular axis. For example, GLP-1 stimulates insulin secretion and decreases hepatic glucose output and insulin resistance in the liver and adipose tissues. GLP-1 also decreases steatosis via activation of genes such as PPARα/γ that enhance hepatic fatty oxidation, lipid export, and insulin sensitivity. GLP-1 lowers liver inflammation via the attenuation of TNFα, IL6, IL-1β, and MCP-1 expression [[2]Kim Y.O. Schuppan D. When GLP-1 hits the liver: a novel approach for insulin resistance and NASH.Am J Physiol Gastrointest Liver Physiol. 2012; 302: 759-761Crossref Scopus (30) Google Scholar]. More recently, GLP-1 appeared to reduce fatty-acid-related hepatocyte death through activation of macro- and chaperon-mediated autophagy that reduces endoplasmic reticulum stress and liver fatty acid accumulation responsible for apoptotic liver injuries [[3]Sharma S. Mells J.E. Fu P.P. Saxena N.K. Anania F.A. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.PLoS One. 2011; 6: e25269Crossref PubMed Scopus (200) Google Scholar]. RYGB also affects insulin resistance through an increase in adiponectin and changes in gut microbiota secondary to alterations in bile and nutrient flow. The new intestinal microbiota, with fewer Firmicutes and more Proteobacteria, change energy metabolism, directing oligosaccharide metabolism to higher production of short-chain fatty acids (propionate, acetate, etc.) that stimulate expression of key mediators of insulin sensitivity (see Fig. 1) [[4]Li J.V. Ashrafian H. Bueter M. Kinross J. Sands C. le Roux C.W. et al.Metabolic surgery profoundly influences gut microbal-host metabolic cross-talk.Gut. 2011; 60: 1214-1223Crossref PubMed Scopus (330) Google Scholar]. Between 85% and 90% of bariatric surgery candidates have steatosis, which can be severe (i.e., present in more than two-thirds of hepatocytes) in 27% of them [5Lassailly G. Caiazzo R. Hollebecque A. Buob D. Leteurtre E. Arnalsteen L. et al.Validation of noninvasive biomarkers (Fibrotest, Steatotest and NashTest) for prediction of liver injury in patients with morbid obesity.Eur J Gastroenterol Hepatol. 2011; 23: 499-506Crossref PubMed Scopus (70) Google Scholar, 6Mathurin P. Hollebecque A. Arnalsteen L. Buob D. Leteurtre E. Caiazzo R. et al.Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.Gastroenterology. 2009; 137: 532-540Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar]. Meta-analysis revealed steatosis improvement in 90% of cases after surgery [[7]Chavez-Tapia N. Tellez-Avila F. Bariatric surgery for non-alcoholic steatohepatitis in obese patients.Cochrane Database Syst Rev. 2010; 20: CD007340Google Scholar]. The improvement occurred within the first year and persisted up to five years. Mechanisms involved in the evolution of both insulin resistance and steatosis are intimately connected. Indeed, bariatric surgery is a powerful treatment for insulin resistance, with remission of type 2 diabetes occurring in 42% of cases after RYGB [[8]Schauer P.R. Kashyap S.R. Wolski K. Brethauer S.A. Kirwan J.P. Pothier C.E. et al.Bariatric surgery versus intensive medical therapy in obese patients with diabetes.N Engl J Med. 2012; 366: 1567-1576Crossref PubMed Scopus (1610) Google Scholar]. Patients with insulin resistance refractory to surgery have a probability of presenting with severe steatosis that is twice as high as that of patients with improved insulin resistance [[6]Mathurin P. Hollebecque A. Arnalsteen L. Buob D. Leteurtre E. Caiazzo R. et al.Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.Gastroenterology. 2009; 137: 532-540Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar]. Moreover, weight gain relapse occurs in 46–63% of subjects two years after bariatric procedure. As surgical success is linked to drastic changes in eating habits, weight gain may be secondary to psychological disorders, dilatation of the gastric pouch, an increase in volume intake or a sedentary lifestyle [[9]Freire R.H. Borges M.C. Alvarez-Leite J.I. Toulson Davisson Correia M.I. Food quality, physical activity, and nutritional follow-up as determinant of weight regain after Roux-en-Y gastric bypass.Nutrition. 2012; 28: 53-58Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar]. As a consequence, future prospective studies must evaluate its impact on liver injury over a follow-up of longer than 5 years. Cochrane meta-analysis was unable to evaluate the specific impact of bariatric surgery on NASH features [[7]Chavez-Tapia N. Tellez-Avila F. Bariatric surgery for non-alcoholic steatohepatitis in obese patients.Cochrane Database Syst Rev. 2010; 20: CD007340Google Scholar]. Indeed, most studies had insufficient sample sizes and their designs lacked sequential biopsies focusing on NASH patients. In a princeps study of 23 NASH patients treated with LAGB, necro-inflammatory activity and fibrosis improved in approximately 80% of cases [[10]Dixon J.B. Bhathal P.S. Hughes N.R. O’Brien P.E. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss.Hepatology. 2004; 39: 1647-1654Crossref PubMed Scopus (645) Google Scholar]. Other clinical and experimental studies showed the same trend in improvement of NASH and a decrease in key inflammatory mediators such as IL8 and MCP1 (measured by RT-PCR from liver samples) [[11]Klein S. Mittendorfer B. Eagon J.C. Patterson B. Grant L. Feirt N. et al.Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease.Gastroenterology. 2006; 130: 1564-1572Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar], but their sample sizes were insufficient for obtaining valid conclusions (Table 1).Table 1Evolution of histological features following bariatric surgery. Open table in a new tab Concern about worsening of fibrosis stems from ileojejunal bypass, a no-longer-used procedure that produced up to 7–10% cirrhosis at long term (5 years), related, in part, to bacterial overgrowth and translocation [[12]Hocking M.P. Duerson M.C. O’Leary J.P. Woodward E.R. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases.N Engl J Med. 1983; 308: 995-999Crossref PubMed Scopus (171) Google Scholar]. Recent procedures do not appear to be associated with development of extensive fibrosis [[10]Dixon J.B. Bhathal P.S. Hughes N.R. O’Brien P.E. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss.Hepatology. 2004; 39: 1647-1654Crossref PubMed Scopus (645) Google Scholar]. A slight increase in fibrosis in patients who were poor responders to bariatric surgery has been described. A decrease in collagen-alpha-1, TGFβ1, SMA, a tissue inhibitor of metalloproteinase 1 expression and SMA content (measured by RT-PCR from liver samples), supports the beneficial effects of current surgical procedures [[11]Klein S. Mittendorfer B. Eagon J.C. Patterson B. Grant L. Feirt N. et al.Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease.Gastroenterology. 2006; 130: 1564-1572Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar]. Nevertheless, additional studies are required to determine whether fibrosis progresses in patients treated with current surgical procedures. Severely obese cirrhotic patients, as compared to non-cirrhotic and non-obese cirrhotic patients, have the highest risk of mortality and require a specific therapeutic strategy possibly involving bariatric surgery. However, such an approach warrants discussion. Indeed, malabsorptive procedures are less suitable for cirrhotic patients in light of their nutritional status, increased surgical complexity, and absorption of drugs, particularly immunosuppressive molecules in the case of liver transplantation. Decompensated cirrhotic patients are contraindicated for bariatric surgery because of the 21-fold increase in postoperative mortality following bariatric procedures [[13]Mosko J.D. Nguyen G.C. Increased perioperative mortality following bariatric surgery among patients with cirrhosis.Clin Gastroenterol Hepatol. 2011; 9: 897-901Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. Moreover, the 2-fold mortality increase observed for compensated cirrhotics compared to non-cirrhotics in the national US database (but not confirmed in other series) emphasized that selection criteria for bariatric surgery candidates remain to be sharply defined [[13]Mosko J.D. Nguyen G.C. Increased perioperative mortality following bariatric surgery among patients with cirrhosis.Clin Gastroenterol Hepatol. 2011; 9: 897-901Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. For some experts, for example, portal hypertension evaluated by CT scan and endoscopy, a previous episode of hepatic decompensation or biological signs of hepatic insufficiency would exclude the possibility of bariatric surgery. All these questions warrant further study. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.