286 J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran. The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing due to increasing of morbid obesity prevalence worldwide. It has been demonstrated that weight loss is the corner stone of NAFLD/NASH treatment. Various options are available for weight loss in obese patients, such as life style modification, pharmacotherapy, endoscopic interventions and bariatric/metabolic surgery. Performing bariatric/meta bolic surgery only for NAFLD/NASH treatment is on debate, but it has been proven that bar iatric surgery is the most durable and effective treatment for weight loss and obesity-related comorbidities. Keywords bariatric surgery, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, weight loss, obesity, insulin resistance, lifestyle Introduction Because of high fat source diet and sedentary life style which is more common recent years obesity and morbid obese population has been rapidly increased.1 According to national health and examination survey, the obesity preva- lence between 20 to 74 years has been risen from 15 to 32.9%.2 Visceral fat accumulation in liver tissue named non- alcoholic fatty liver disease (NAFLD), known as a component of metabolic syndrome includes type 2 diabetes, hypertension and dyslipidemia represented insulin resistance (IR).3 NAFLD that is considered the liver phenotype of meta- bolic syndrome is the most common cause of liver dysfunction and with a prevalence of 6.3–33% worldwide.1 The first sign of NAFLD is accumulation of hepatic fat (steatosis) that progress to non-alcoholic steatohepatitis (NASH), liver inflammation, fibrosis, cirrhosis and hepatocel- lular carcinoma.4 Current NAFLD and NASH treatments include weight loss obtained by life style modification and pharmaceuti- cals but have poor effects in patients with body mass index >35 kg/m2.5 Some evidences showed bariatric surgery (BS) could alter the course of disease.6 Now a days weight loss surgery considered unique method to obtain durable and permanent weight loss in morbid obesity obese could reverse metabolic syndrome consequences as well as fatty liver disease, improve liver histopathology and improve insulin resistance (IR).7 According to recent evidences we search database to approve our thesis on positive impact of BS for reversing negative metabolic syndrome effects of liver function and histopathology. Methods We searched PubMed, Scopus and google scholar with these at Nov 1, 2016. We found 772 papers. After deleting duplicate papers in searches (429 papers), finally 518 papers remained. 346 articles were related to our subject based on their titles and abstracts. We used only papers that their full-text was related to our title. Results Prevalence of NAFLD and NASH in Bariatric Candidates NAFLD, as an emerging clinical implication, is most closely associated with obesity.8 The prevalence of obesity, as a med- ical and societal problem, is increasing around the world, even in developing countries.8,9 Morbid obesity (Body Mass Index (BMI) > 40 kg⁄m2) is treated with the suggested weight loss interventions such as BS.9 NAFLD prevalence is much higher in obese (BMI > 30 kg⁄m2) patients.9 A prospective cohort study indicated that 70% of the patients who were obese and candidate for BS, pre- sented steatosis, a liver damage pattern of NAFLD.10 However, Results from different studies show that the prevalence of NAFLD varies between 16.7% and 96% in morbidly obese patients subjected to bariatric surgery.10–22 The wide range of NAFLD prevalence depends on the biochemical criteria and the method sensitivity used to detect NAFLD.8,23 Furthermore, NASH, as a progressive manifestation of NAFLD, occurs in 7.3% to 98% of such patients.10,12,13,17,18,20–22,24–30 The study which reported NASH in 98% of their patients, indi- cated that the mean super obese state (Mean BMI 52.8 kg ⁄m2) in their population is the reason of high NASH prevalence.30 Another study concluded that the differences in NASH preva- lence can be explained by the histological criteria used to diag- nose NASH.22 Ethnicity affects NAFLD prevalence as well.23 In a study on morbid obese patients underwent BS, African-American patients had lower NAFLD and NASH rate than Non- Hispanic whites and Hispanics. Non-Hispanic white and Hispanic patients had similar NAFLD prevalence. They suggested ethnic differences in fat distribution as an explanation for lower NASH rate in African-Americans.31 Bariatric Surgery and Metabolic Syndrome Metabolic syndrome is characterized by central obesity, hyper- triglyceridemia, low high density lipoprotein cholesterol (HDL-C), high blood pressure and high fasting plasma glucose.32 ISSN 2413-0516 Review a b Center of Excellence of European Branch of International Federation for Surgery of Obesity, Tehran, Iran. c Medical Student Research Committee, Iran University of Medical Sciences, Tehran, Iran. Correspondence to: Ali Kabir (e-mail: aikabir@yahoo.com). (Submitted: 04 July 2017 – Revised version received: 22 July 2017 – Accepted: 10 September 2017 – Published online: 26 December 2017) Role of bariatric surgery in treatment of non-alcoholic fatty liver disease Mohammad Kermansaravi,a,b Mohammad Ebrahimian,c Delaram Delbari,c Simin Khamoushi,c and Ali Kabira Mohammad Kermansaravi et al. 287J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Research Role of bariatric surgery in treatment of non-alcoholic fatty liver disease BS is considered a safe and efficient treatment of metabolic syndrome.8 In a study of 46 morbid obese patients subjected to laparoscopic gastric bypass, metabolic syndrome and some of its components including hypertension, dysglycemia and dys- lipidemia and IR were resolved after 2 years.33 Similar results were observed in a study of 827 patients who underwent laparo- scopic Roux-en-Y gastric bypass (RYGB) with 4 years follow ups.34 However, improvement of metabolic syndrome is most likely associated with the amount of excess weight loss.35 Insulin Resistance IR is considered to be the hallmark of metabolic syndrome.36 The measure of insulin sensitivity indices has shown a reduced mean insulin sensitivity in nonobese, non-diabetic young sub- jects with NASH in association with the different components of the metabolic syndrome. A small study of nondiabetic severely obese patients revealed that biliopancreatic diversion (BPD) improves insulin sensitivity four days after the operation. They suggested that this sharp improvement might be explained by the intramyo- cellular fat depletion and enteroinsular axis interruption.37 In another study, patients who underwent gastric bypass surgery (BMI approximately 30 kg/m2) had greater insulin sensitivity than weight-matched group (BMI = 25 to 35 kg/m2).38 Simi- larly, Klein et al. demonstrated that gastric bypass (GBP)- induced weight loss markedly improves hepatic insulin sensitivity and metabolic abnormalities related to NAFLD. A decrease in intrahepatic free fatty acid (FFA) availability, caused by decreased release of FFA from intrahepatic, visceral, and subcutaneous fat is considered to be the probable explana- tion for marked improvement in insulin action.39 Association between NAFLD and Type 2 Diabetes and the Role of Bariatric Surgery A study on patients who underwent jejunoileal bypass (JIB) found a decrease in fasting blood glucose and improvement in type 2 diabetes after JIB. In their study, NAFLD was observed in 86.7% of patients and NASH in 31.7%.40 In a retrospective study, 88.7% of patients who under- went BS and did not have diabetes and hypertension, showed liver steatosis. 7.3% of these individuals had NASH and 19.3% had liver fibrosis. Furthermore, they found liver steatosis in 96%, NASH in 22% and liver fibrosis in 30.6% in the presence of diabetes and hypertension.20 In a study of 112 morbid obese patients underwent bari- atric surgery, 57.7% of patients presented NASH. In these patients, type 2 diabetes was significantly (P value = 0.018) associated with the NAFLD type 4 which is considered as NASH.29 Bariatric Surgery for Treatment of NAFLD/NASH in Pediatrics and Adolescents A recent study on obese adolescents who underwent laparoscopic sleeve gastrectomy (SG) found complete improvement of NASH in all patients and reversed hepatic fibrosis stage 2 in 90%.41 The Role of Obstructive Sleep Apnea (OSA) in NAFLD and Its Improvement Following Bariatric Surgery In a study by cottam et al., patients with fatty liver disease and comorbid conditions underwent a two stage approach; laparo- scopic SG as the first stage and laparoscopic RYGB as the second one. All cases of diabetes had improvement prior to the second stage and almost all patients with sleep apnea had resolution or improvement. Their study demonstrates that proceeding directly with a RYGB probably is not a safe option.42 A cohort study by benotti et al. showed that the severity of OSA is associated with the NAFLD severity in severe obese patients without metabolic syndrome. They concluded that the intermittent hypoxia followed by the OSA severity may be linked with the pathogenesis of NAFLD.43 Indications of Bariatric Surgery in NAFLD/NASH NASH/NAFLD as an independent indication for bariatric/ metabolic surgery is controversial.15 Based of new statements of IFSO (International Federa- tion for the Surgery of Obesity and Metabolic Disorders), bar- iatric surgery leads to improvement and resolution of NAFLD and NASH in morbid obese patients.44 Because obesity, diabetes mellitus and hyperlipidemia (HLP) are among the risk factors for the NAFLD progression, so, weight loss induced surgery, improves these comorbidities together with NAFLD.45 Actually, the indications of surgery in NAFLD/NASH are the same as in morbid obesity and are BMI equal or more than 40, or 35 < BMI < 40 with any evidence of metabolic syndrome or related comorbidities.5,46 Also bariatric surgery is indicated in overweight patients with medical-resistant severe metabolic complications.46 Types of Bariatric Surgeries There are three different types of bariatric surgery:8,47–49 1. Restrictive procedures that create a state of satiety and decrease the gastric capacity and including: a. Sleeve gastrectomy (SG): Creation of a lesser curve based narrow gastric tube, on a sizer bougie from 4–6 cm of pylorus up to gastroesophageal junction and resection of about 80% of stomach. b. Adjustable gastric banding (AGB): Placement of an adjustable band around the upper part of stomach to create a small pouch. c. Vertical banded gastroplasty (VBG): Creation of stapled upper part of stomach in lesser curvature that is sup- ported by an extra luminal band. 2. Malabsorptive procedures, such as biliopancreatic diver- sion with or without duodenal switch (BPD-DS), that create a near 200 cc tube of stomach like SG, but preserves the pylorus and cut the duodenum 3–4 cm after pylorus and then create a Roux-en-Y dudenojejunostomy with short common limb. These procedures alter the food and calorie intake and absorption. 3. Combined or mixed procedures such as Roux-en-Y Gastric bypass (RYGB), that create a stapled small proximal gastric pouch with well-nigh 30 cc capacity that is anastomosed with two limbs of jejunum in RY fashion. Comparison the Effectiveness of Different Methods of Bariatric Surgery in NASH/NAFLD In general, bariatric surgery leads to weight loss, decreasing of transaminases and improvement of NAFLD.50 New studies show that bariatric surgery can improve the histologic features of steatosis, hepatocyte ballooning and lob- ular inflammation, but it effect in liver fibrosis is on debate.51 288 J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Role of bariatric surgery in treatment of non-alcoholic fatty liver disease Research Mohammad Kermansaravi et al. Bariatric surgery can also lead to significant improvement of liver function but if initial weight loss is too much and BMI loss is greater than 80%, can worsen the liver function that is usually improved after one year after surgery.25 Continue to investigate the effect of two more common surgical methods throughout the world and comparing them with other relatively conventional methods described above. 1. RYGB: This method of surgery stimulates GLP-1 secretion that leads to significant improvement of some obesity-related syndromes, such as IR, inflammation and steatosis, that stea- tosis and also fibrosis improvement is due to decreasing of fat droplet accumulation in the liver and improvement of mito- chondrial function.52 Also RYGB can correct the bile secretion derangement.53 The PYY (peptide YY) hormone secretion is increased and ghrelin hormone is decreased in this method and along with Glp-1 secretion induces the satiety state.54 There are some evidences that confirm a strong associ- ation between liver fat content reduction and IR correction in RYGB even before remarkable weight loss.55 Víctor Vargas et al. performed one liver biopsy during RYGB and another biopsy in percutaneous method, 12–22 months after surgery. They found significant histopathologic improvement in liver steatosis, ballooning degeneration, portal inflammation and fibrosis that were statistically significant.48 Joshua S Winder et al, in a study in USA, reported NAFLD improvement based on Computed Tomography (CT) scan, in 84.2% of patients after LRYGB.56 Another study that is done by Jeanne M. Clark, et al., reported improvement of all morphologic indicators of NAFLD after RYGB and 81% of patients had complete remis- sion of liver steatosis and there were no worsening of these indicators.57 Carlos K Furuya Jr, et al., in a study performed percuta- neous liver biopsy, 2 years after RYGB and reported significant improvement of steatosis (89%), liver fibrosis (75%) and hepa- tocellular ballooning (50%) after surgery.7 Everton Cazzo et al., found improvement of advanced liver fibrosis in 55% of patients, one year after LRYGB that were sta- tistically correlated with female gender, EWL percentage, post op BMI, post op platelet and improvement of T2DM.58 Kevin B. Barker et al., in their study, resulted in significant improvement of steatosis, lobular inflammation and periportal fibrosis and improvement of NASH in 89% of patients after RYGB. 59 The study of Xiuli Liu et al., liver biopsy, showed signifi- cant improvement in macro steatosis (97%), micro steatosis (87%), hepatocellular ballooning (100%) and regression of liver fibrosis, about 18 months after RYGB and notified that rapid weight loss, not only not lead to worsening of hepatocel- lular injuries and progression of fibrosis, but also can lead to improvement of steatosis.60 Soraya Rodrigues de Almeida, et al, in a study, notified complete improvement of NAFLD in 93.7% and lobular inflammation in 100% of patients after nearly 23.5 months after RYGB.61 2. Sleeve gastrectomy (SG): Sleeve gastrectomy is another effective method for weight loss and NAFLD improvement. In a retrospective study, Ardeshir Algooneh et al., reported complete remission of NAFLD in 56% of patients and had a strong correlation with post op BMI, that most of NAFLD remissions were occurred in post op BMI: 25–30.62 Melania Manco et al., found 100% improvement of NASH in adolescents, one year after SG and in their study, SG was most effective than lifestyle change and intragastric weight loss device.41 Another study resulted in improvement of liver steatosis (66.6%), fibrosis (68%) and NAFLD activity score, 3 months after SG.63 Comparing SG with RYGB A recent study, in 35 patients with T2DM and BMI > 35, demonstrated that after 12 months after surgery, SG was signif- icantly most effective on LFTs than RYGB (P: 0.007), also had better effect on NAFLD improvement, in spite of the fact that glycemic control were the same.64 Another study displayed better effect of alanine ami- notransferase (ALT) improvement after SG in comparison with RYGB, but more impact for RYGB in liver fibrosis and NAFLD regression.65 Comparing RYGB and LAGB In a study in France, who performed in 109 patients, the inves- tigators found that RYGB resulted in more statistically signifi- cant effect in weight loss and NASH improvement in comparison with Laparoscopic Adjustable Banding (LAGB).46 Another study in 1236 patients, between 1996 to 2012, was done with one and five years follow ups, disclosed that RYGB had significantly better effects on NAFLD and liver his- tology that LAGB.66 Other Surgical Methods VBG Charalabos Stratopoulos, et al., in a study in 51 patients, that underwent VBG, with liver biopsy, 18 months after surgery demonstrated improvement of steatohepatitis un 86.2% patients, but unchanged liver fibrosis in 41.1% of cases and worsening of liver fibrosis in 11.7% of patients, however they didn’t see any progression to cirrhosis.30 Duodenal Switch (DS) Ara Keshishian et al., in a study showed that DS lead to improvement of liver steatosis and inflammation, but the patients had a transient worsening in Aspartate Aminotrans- ferase (AST) and ALT levels, in 6 month after surgery that became normal after one year. In this study after 3 years follow up, the patient had progressive improvement of NASH.67 Complications of bariatric surgery General complications Different degrees of deficiencies in Iron, folate, vitamins and trace elements are seen in all bariatric surgeries.68 Gastric and anastomosis ulcers, bile reflux, dumping syndrome, adhesions, nausea and vomiting, wound infec- tion, pulmonary emboli, abscess, inadequate weight loss and weight regain, may be present in many of bariatric procedures.69 Also in some patients that have poor response to bariatric surgery, mild increasing in liver fibrosis may occur.70 Mohammad Kermansaravi et al. 289J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Research Role of bariatric surgery in treatment of non-alcoholic fatty liver disease Procedure specific complications 1. LAGB: Band slippage, band erosion, band migration, gas- tric pouch dilatation and malfunction of band’s port and tube are some of LAGB specific complications.49 2. SG: Bleeding, leak, GERD, antral stenosis, functional stenosis, portal thrombosis and renal failure are some of Laparo- scopic Sleeve Gastrectomy (LSG) related complications.42,49,71 3. BPD/DS: GI obstruction, leak, peptic ulcer disease, pro- tein malnutrition, fat soluble vitamin deficiencies, nutri- tional derangements, transient worsening of NASH, worsening of NAFLD and liver histology due to severe weight loss and risk of bacterial stasis and overgrowth due to blind loop syndrome are specific complications of BPD/DS.46,48,49,67,68,72 4. RYGB: GI obstruction due to internal hernia, leak, malnu- trition, bleeding and leak are some specific complications of RYGB.49 Potential Mechanisms of Bariatric Surgery in NAFLD/NASH Treatment 1. Improvement of IR: Weight loss, reduction of visceral lipids, increasing of GLP-1, improvement of bile acid metabolism 2. Improvement of dyslipidemia: Decreasing of LDL, HDL, TC and increasing of HDL 3. Alterations of gut hormones: Decreasing of ghrelin and increasing of GLP-1, PYY, Oxyntomodulin and bile acids 4. Decrease of inflammation: Decreasing of Interleukins 1 and 8, CRP and TNF-α 5. Decrease of leptin and increase of adiponectin 6. Decrease of hepatocellular apoptosis and oxidative stress of endoplasmic reticulum 7. Weight loss and BMI loss: Improvement of these major risk factors for NAFLD/NASH 8. Desirable modifications in gut microflora22,45,47,49,55,73–76 Selecting the most suitable bariatric procedure in treatment of NASH/NAFLD Weight loss is a mainstay and gold standard method for NAFLD/NASH treatment.5,62 Bariatric surgery procedures as other weight loss programs are effective in improvement of NASH/NAFLD, but are significantly most effective than non-surgical procedures such as, medical drugs and life style modifications.41,77,78 Till now, the best surgical procedure for NAFLD/NASH is not determined and meta analyses, show that all bariatric surgical procedures lead to NAFLD/NAFLD improvement in obese patients and liver steatosis in most of this patients (near 90%).47,64,70,79 Recent studies demonstrated that bariatric surgery; result in improvement of biochemical and histologic parameters of liver, such as non-alcoholic steatosis and steatohepatitis, liver fibrosis, lobular inflammations, chronic portal inflammations and even hepatocellular carcinoma.47,55,62,79,80 Selection of bariatric surgery procedure must be done based on other conditions and indications and also need to have regular and punctual follow up after surgery.81 In confirmed NAFLD or patients that are at risk of advanced NAFLD, as possible, must avoid of malabsorptive procedures such as BPD/DS due to rapid and severe weight loss that result in FFA rapid releasing and transfer of long chain fatty acids to liver and bacterial over growth that can lead to worsening of NAFLD.5,48,72 Long-term Effects of Bariatric Surgery in NAFLD/ NASH Treatment It seems that, bariatric surgery has durable and long standing effects in NAFLD/NASH; however, it needs to perform more related studies with longer follow ups. Anne-Sophie Schneck et al., performed a study that had a mean 55 month follow up after RYGB, and resulted in durable improvement of liver injury, hepatocytes apoptosis, steatosis, inflammation, NAFLD activity score (NAS) and liver fibrosis in 88% of patients till that time of follow up.82 Swedish Obese Subjects (SOS) Study, that was done in ret- rospective fashion in a total of 3,570 obese participants, that were divided in two surgical(AGB, VBG, Bypass) and non-sur- gical groups, with 10 years follow ups, demonstrated improve- ment of transaminase levels only in surgical group that had positive correlation with weight loss. This study resulted that the short-term effects of bariatric surgery are durable and per- sistent in long time after surgery and have long standing pro- tective effect against chronic liver injuries.50 Non-surgical treatment (endoscopic) of NAFLD/ NASH Instead of bariatric surgery with different complications, there is an option to choose less invasive gadgets like endoscopic therapies with lower cost and risks55 including the endoscopic duodenal–jejunal bypass liner (DJBL),83 intragastric balloon therapy,55 and the bioenterics intra gastric balloon (BIB) are present. DJBL first motivation was to treat obesity, however, it turned out that it also leads to:83 1. Significant weight loss 2. Improvement of type 2 diabetes 3. Decrease of plasma liver parameters (normalizing of AST, ALT, andg-GT and caspasecleaved CK-18) which indicates regression of NASH Genco A, showed that BIB reduces BMI84 and improve- ment of metabolic profile85 even though there hasn’t been any researches done on NAFLD status. it could also be used in patients with lower levels of obesity.49,86 Response to bariatric surgery (biopsy, MRI, CT) Biopsy Biopsy As the gold standard10 has different complications, including bleeding, pain, hypotension, hemorrhage, bile perito- nitis, pneumothorax, hemothorax, transient bacteremia, hemo- bilia, tumor seeding and death.87 The size of the biopsy obtained can be a better representive of liver tissue.88 Computer tomography Suitable for steatosis but not for visualizing inflammation of liver and early stages of fibrosis.10 Since weight of scanner could be a limitation, CT might not be achievable.25 MRI Able to detect hepatic triglyceride (hepatic fat), concentration in NAFLD and monitor liver steatosis, as non-invasive 290 J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Role of bariatric surgery in treatment of non-alcoholic fatty liver disease Research Mohammad Kermansaravi et al. technique following bariatric surgery (BS), after one year a decrease in liver fat was seen.89 LiMAx test It can determine capacity of enzymatic liver function based on hepatic 13 C-methacetin metabolism by the cytochrome P450 1A2 system. repetitive testing will monitor disease course and response to BS.25 Transient hepatic elastrography Fibrosis of liver has a significant relation with elasticity that is detected by this new method.25 Effectiveness of Surgical and Non-Surgical Ways of Weight Reduction in NAFLD Treatment Before any recommendations, since weight loss should be included as background therapy in every protocol for NAFLD treatment.90 Bariatric surgery (BS): As average, 12 months after BS, BMI decreased to 11.9 kg/m and NASH was cleared in 85% of patients. Life style alteration: a healthy lifestyle results in improve- ment of NASH and macroinflammation91 also a reduction in oxi- dative stress.92 In a Cuban population a 5% reduction of weight and 25% resolution of NASH was seen.93 In a study done by St George patients were randomized in three groups moderate (6 sessions), low (3 sessions) intensity and control, a remarkable decrease of liver enzymes were seen in moderate intensity altera- tion94 but the stage of fibrosis is yet to be experimented. •   Dietary  limitation:  By  MRI  measurement  every  5%  decre ase in BMI equals 25% in liver fat induced by hypocaloric diet.90 •    Physical  activity:  day  to  day  used  calories  by  physical  activity are restricted compared with what is achieved by dietary limitation. When it is integrated with diet from the starting point of behavior treatment, it might have more favorable outcomes,90 such as reduction of hepatic stea- tosis, liver lipids and improvement of insulin resistance.95 •   Behavioral therapy. It is burdensome for the greater part of individuals to change their life style, including their diet and physical activity.90 Weight regain is not uncommon after medical treat- ment. Lifestyle modifications when combined with pharmaco- therapy have more favorable outcomes.96 Probiotics as regulators for energy hemostasis are associated with better liver enzyme status and histology.97 •  Statins can be used in patients with dyslipidemia and  NAFLD to reduce steatosis.98 •  Orlistat:  it  decreases  BMI,  but  has  gastrointestinal  side effects like, flatus and diarrhea.99 •  PUFA: improves both liver stestosis and biochemical  features of NAFLD.100 •  Vitamin E: it is not recommended in diabetic patients  or those with cirrhosis, it decreases the activity of hepatic profibrogenic actions.101 What lies ahead of bariatric surgery in NAFLD patients? Several retrospective and prospective cohort studies has been done to clarify the optimal surgical treatment, nevertheless the gap that requires filling, is the Randomized Clinical Trial (RCT) part. Since nowadays bariatric surgery is used as a new treatment for NAFLD in obese patients, we need more long- term evidences (10 year outcomes), to find the most suitable procedure and estimation of its costs. Nutrient Deficiency and Rapid Weight Loss? A Negative Factor of BS, How to Prevent? Type of surgical procedure, pre operative deficiencies, contin- uous post operative vomiting, modified eating habits and food intolerance could have direct relation with the risk of nutri- tional deficiency after BS, so, patients should be monitored for rapid weight loss after BS especially with alarm symptoms such as: nausea, vomiting, and abdominal pain.102–104 Also vita- mins and supplement malabsorption, can lead to nutritional deficiencies.105 Anemia due to iron, folic acid and vitamins B12, C and D (50–80% of BS patients)106 deficiencies107 and Iron deficiency which is common after gastric bypass.108 There are many concerns that rapid weight loss, may have a role in worsening of NAFLD,102,109 however Mathorin reported that in 95.7% of patients fibrosis score was not higher than 1.110 To prevent the post operative effects and improve long-term outcomes of BS, it is obligatory to: 1. Screening of nutritional state 2. Prevention of nutrient deficiencies by prescribing appropriate supplementation, in pre and post-surgical stages.106 Alternatives Managing patients with NAFLD contains treatment of liver disease and metabolic comorbidities, that focuses on weight loss which are achieved through hypocaloric diet or increased physical activity.111 Also daily usage of vitamin E improves his- tology of liver in non-diabetic adults with biopsy -proven NASH, therefore it is not recommended for patients with NASH cirrhosis, or cryptogenic cirrhosis.112 Unfortunately, there is inadequate evidences to support metformin, thiazolidinediones, bile acids, or antioxidant sup- plements for NAFLD treatment. Bariatric Surgery and Long-term Effect on Liver Function Tests •  ALT,  AST,  caspase-cleaved  CK-18  and  GGT  decreased  3 months after duodenal–jejunal bypass and only per- manent reduction in ALT and GGT was seen in 6 months later.83 •  Intragastric  balloon  and  minimum  weight  loss  of  10%  decrease ALT and Gamma-Glutamyl Transferase (GGT) in a study by Ricci et al.3 •  Patient  undergoing  BPD-DS  and  RYGB  after  3  years  showed sustained reduction in BMI, ALT, and GGT. but decrease in platelet counts only occur in BPD-DS group which reflects decrease in liver fat content related inflam- mation and lower secondary thrombocytosis.113 •  Significant reduction in ALT and AST seen in Vergas et al.  study by restrictive malabsorptive procedures.48 •  Preoperative AST levels and excess weight loss were associ- ated with improvement in NASH grade score. There was no significant difference in improvement in stage between the restrictive and gastric bypass group. But there was a trend for better results in the bypass group.114 •  Significant  improvement  in  NASH  was  detected  by  the  enzymatic capacity of cytochrome P450 1A2.25 Mohammad Kermansaravi et al. 291J Contemp Med Sci | Vol. 3, No. 12, Autumn 2017: 286–294 Research Role of bariatric surgery in treatment of non-alcoholic fatty liver disease •  Short-term  worsening  of  AST  and  ALT  levels  at  first  6 months after duodenal switch operation seen in Kesh- ishian et al. study which normalize in 6 months later.67 Changes of liver histopathology after bariatric surgery •  Overall improvement in NAFLD aspects was reported after  BS also improvement in NASH and its related parameters116 but portal abnormality remains unchanged in Dixon et al. study.115 •  Restrictive  mildly  malabsorptive  (gastric  bypass)  proce- dures caused improvement in steatosis, ballooning degen- eration, Mallory bodies, glycogen nuclei, Lobular inflam mation, portal inflammation, and fibrosis. In a study 5 of 26 patient fibrosis persisted and 15.3% of them had NASH in second biopsy.48 •  After  2  years  of  RYGB  and  weight  loss  of  60%  steatosis  and fibrosis disappeared with no worsening and liver biochemical markers found within normal.7 •  RYGB improves lobular inflammation, portal, and lobular  fibrosis in Barker et al. study. There were no significant dif- ferences in serum aminotransferase levels. Two of nine- teen patients still had histopathological features of NASH. One had no significant difference in portal inflammation evidence of cirrhosis and had two points improvement in steatosis and inflammation scores, the second still had evi- dence of mild NASH. This case had weight loss of 54 and 55 kg, respectively, over 2 year period prior to follow- up biopsy.59 •  Excess weight loss of 66% as a result of VBG leads to stea- tohepatitis improvement which correlated with reduction of BMI and ALT. Although overall decrease in fibrosis, 41% didn’t change in fibrosis and 11.7% increase in fibrosis scores.30 •  Major improvements in lobular steatosis, necroinflamma- tory changes, and fibrosis after laparoscopic adjustable gas- tric band placement in Dixon et al. occurred. In this study, no progression of histological parameters occurred.115 •  LRYGB  significantly  improves  the  overall  centrilobular/  perisinusoidal fibrosis scores and also induces regression of centrilobular/perisinusoidal and stage of fibrosis in NASH. However, no changes were noted in fibrosis or inflammation in the portal area after rapid weight loss after LRYGB and no worsening of hepatocellular injury or fibrosis.22,57,61,114 •  De almedia et al. observed 1 complete remission, 1 fibrosis  improvement and 2 cases without any changes in initial liver biopsy among 4 patients presenting fibrosis preoperatively.61 •  In study of Mathurin et al. with Five years follow up almost  all patients had low levels of NAFLD. Slightly increase in fibrosis and long-term improvements in Steatosis and bal- looning that predicted by IR levels was seen.117 •  Lobular fibrosis scores had two stages improvement in 2/19  patients and one stage in 8/19 patients. Only in one patient lobular fibrosis get worse.59 •  Hepatic left lobe volume as hepatic fat indicator reduces  after weight loss achieved by LAGB.118 •  Duodenojejunal  Bypass  surgery  in  rats  nourished  by  western diet normalized serum Triglyceride (TG) and attenuated accumulation of TG and steatosis in the liver of.4 Impact of Bariatric Surgery on Inflammation Markers •  Serum  CD163  levels  increase  with  severity  of  NAFLD  and reduce after weight loss even in severe liver injury indicating reversibility of macrophage activation.119 •  Soluble  CD14  receptor  (sCD14)  and  human  neutrophil  alpha-defensins (HNDs) known as participants in hepatic necro inflammation process reduce following bilio- pancreatic diversion markedly correlated with improvement in NAS score.120 •  Fibrogenesis  regulating  factors  and  regulating  inflam- mation markers which observed one year after gastric bypass such as hepatic collagen-1(I), TGF-β1, α-SMA, and TIMP-1 expression, hepatic α-SMA, hepatic expres- sion of chemokines, MCP-1, and IL-8 declined. At this time marked reduction in steatosis but no change in his- tologic assessments of inflammation and fibrosis was noted.39 •  Three protein peaks observed in obese serum belongs to  hemoglobin subunits increased significantly based on severity of liver lesions (steatosis and NASH) returned to normal values after bariatric surgery. None of them was correlated with metabolic parameters or LFTs.10 Conclusion The pravalence of NAFLD is increasing along the prevalence of morbid obesity worldwide and may leads to NASH in many patients. It is demonstrated that weight loss is the main treat- ment for NAFLD/NASH. There are some options to achieve weight loss and NAFLD improvement, such as life style modification, pharmaco- therapy, endoscopic management and bariatric/metabolic surgery. Although it is controversial to perform bariatric/meta- bolic surgery only for NAFLD/NASH, but it is proven that bar- iatric surgery is the most effective and durable treatment for weight loss and obesity-related comorbidities, also there are some evidences that bariatric surgery lead to decreasing of liver fat content and IR and improvement of metabolic syn- drome, even before significant weight loss. Other studies sug- gest that improvement of metabolic syndrome after bariatric surgery has correlation with amount of weight loss. Also bari- atric surgery with other mechanims, such as altration in gut hormones, changes in gut microflora, reduction of inflamma- tory state and decresing of hepatocellular apoptosis, poten- tially can improve the metabolic syndrome, NAFLD/NASH and liver fibrosis. 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