nonalcoholic fatty liver disease ( nafld ) describes a wide spectrum of liver pathologies from simple steatosis to steatohepatitis ( nash ) and cirrhosis . its prevalence in obese persons is between 50% and 85% , and 6590% in those with type 2 diabetes mellitus ( t2 dm ) .   for patients diagnosed with nash , 1520% may develop cirrhosis . given the fact that patients with nash can enter a final cirrhotic pathway , it is not surprising that nash appears to portend an increased risk of hepatocellular carcinoma . liver function test ( lft ) abnormalities are common in patients with nafld , with elevations in aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) usually no greater than four times the upper limit of normal and a variable ast / alt ratio , although alt usually predominates . it is not clear to date whether biopsy is needed for the diagnosis of nash . the first factor is considered to be insulin resistance resulting in steatosis by increased elaboration of free fatty acids ( ffa ) that are absorbed by the liver . the second factor is a series of complex interactions between hepatocytes , stellate cells , adipose cells , kupffer cells , inflammatory mediators , and reactive oxygen species that result in inflammation ( nash ) or cirrhosis . here , the adipose tissue , whose function goes far beyond gathering energy supplies , seems to play a key role , being an essential endocrine organ producing a number of proteins demonstrating auto- and paracrine effects . unlike other chronic diseases such as t2 dm , there are no formal treatment algorithms for patients with nafld . currently , management of nafld consists of modifying the underlying risk factors including medical therapy [ 914 ] . to induce weight loss in nash patients , sleeve gastrectomy was first introduced by hess and marceau as a restrictive component of biliopancreatic diversion with duodenal switch ; it was initially not intended as a standard single procedure . reported weight loss after isolated sleeve gastrectomy ( isg ) is good and ranges from 33% to 83.3% of ewl at the 1-year followup [ 16 , 17 ] . today sleeve gastrectomy is performed as a stand - alone procedure with a low operative risk . although it is mainly a restrictive procedure , resolution of t2 dm occurs in 50% to over 94% of patients after isg by 1-year followup [ 19 , 20 ] . the impact of bariatric surgery on nash has been examined for several bariatric interventions such as gastric bypass or duodenal switch operations . based on the data reported for isolated sleeve gastrectomy regarding weight loss and amelioration of t2 dm , we examined the effect of isg on nash and nash - related comorbidities using clinical and biological data . a review of prospectively collected data was conducted for 236 consecutive patients , undergoing isg at polyclinique priollet , chlons en champagne , france from december 2002 to september 2009 . data collected included demographic data , preoperative weight / bmi , hba1c levels , liver functions tests ( ast and alt ) , and lipid profiling ( triglycerides , hdl , and ldl ) . early followup examinations were conducted at 6 weeks and 6 months after isg , the later followup time span was yearly . approval for the surgery and prospective audit was granted by the institution 's clinical board . liver biopsy was conducted percutaneously during isg under laparoscopic guidance using a 14-gauge 200  mm tru cut biopsy needle ( carefusion ) . all liver biopsy specimens were stained with h&e , pas , masson trichrome , perls and van gieson . for the assessment of liver histology , one pathologist and a second observer evaluated all biopsies according to the semiquantitative scoring system for nafld proposed by brunt et al . . statistical analysis was conducted using prism 5 for mac os x ( graphpad software , inc . ) spearman 's correlation was applied to asses a correlation between two variables . a p - value <  .05 was considered significant . isolated sleeve gastrectomy was performed in 236 patients with a mean bmi of 45  6.8  kg / m ( table 1 ) . in order to assess liver histology , intraoperative liver biopsy was accomplished in all patients . from the 223 histologic samples that could be finally evaluated , diagnosis was as follows : 35 patients with normal liver , 77 with steatosis , 87 with nash , 18 with fibrosis , 3 with cirrhosis , 2 with siderosis , and one patient with chronic hepatitis   ( table 1 ) . patient followup was conducted up to 3 years with a median overall followup of 12 months . among the clinical and biological data analysed , nash was significantly correlated with higher hba1c , ast , and alt levels and lower levels for hdl ( spearman 's correlation < .05 , < .0001 , < .0001 , < .01 , resp . ) . elevated alt levels could only be detected in 2 of 33 patients with normal liver histology , but in 33 of 65 patients with nash ( fisher 's exact test p < .0001 ) . interestingly , there was a significant correlation between a progressing liver disease from normal liver histology over steatosis to nash and rising hba1c levels ( pearson 's correlation p < .01 ) . our main objective was to determine if nash has an impact on the primary outcome after isg , and equally important to analyze the effect of isg on nash . overall , isg led to substantial weight loss with a bmi reduction of 44% within 1 year ( table 2 ) . comparing patients with normal liver histology to patients diagnosed with nash , a significant reduction of body weight was seen in both groups with a marginally larger preoperative bmi in nash patients ( 44.2  5.6 nonlinear regression analysis suggested equal initial weight loss in both groups with an impaired reduction of bmi for nash patients beginning after the 9-month followup ( plateau 28.08  kg / m versus 29.79  kg / m , figure 1 ) . overall , patients with normal liver histology presented with a significantly better weight reduction ( two - way anova p < .05 ) . histologic evaluation of this subgroup revealed only 2 patients with normal liver histology , 4 with steatosis , 14 with nash , 1 with cirrhosis , 1 with fibrosis , and 1 with chronic hepatitis . there was a highly significant difference in weight reduction compared to non - diabetic patients , ( two - way anova p < .001 ) . nonlinear regression analysis revealed a broader difference in plateau level comparing nash patients to patients with normal liver histology ( plateau for hba1c > 6.5% 32.30  kg / m versus hba1c  6.5% 28.79  kg / m , figure 2 ) .   regarding biological data , isg could significantly improve hba1c levels in all patients ( kruskal - wallis p < .0001 , table 2 ) . in the 23 patients diagnosed with diabetes prior to sleeve gastrectomy , median hba1c levels normalized within 12 months ( hba1c 7.1% versus 5.6% , resp . ) . a significant reduction of hba1c levels could also be shown for nash patients ( kruskal - wallis p < .01 ) . in patients who presented with normal liver histology , sleeve gastrectomy had no effect on hba1c ; however , mean hba1c was not above the cutoff level of 6.5% at any given time point ( table 3 ) . overall mean triglyceride levels could be reduced by 37.5% after 1 year ( table 2 ) . in patients with nash , initial triglyceride levels were higher than in patients with normal liver histology ( 1.8  1.4 although a significant reduction of triglycerides was seen in both groups , nash had a significantly impairing impact on triglyceride levels ( two - way anova p < .05 , table 3 ) . overall , analysis of the remaining lipid profile showed no influence of isg on cholesterol , hdl , or ldl levels ( table 2 ) . in contrast , nash patients presented a significant improvement of hdl ( kruskal - wallis p < .0001 , table 3 ) . transaminase levels were examined as a representative test for liver function and liver injury . in preoperative data , a strong correlation could be seen between high transaminase levels and histologically diagnosed nash ( spearman 's correlation p < .0001 and < .0001 for alt and ast , resp . ) . for patients with nash , transaminase levels could be reduced by over 50% within 6 months , achieving similarity to the levels of patients with normal histology . for patients with normal histology , transaminase levels were low and remained unchanged after sleeve gastrectomy ( figure 3 ) . in the present study , we report a mean bmi loss of 15.3  kg / m and 13.4  kg / m at 12 and 39 months after isg . this goes along with data recently published on 200 patients with isolated sleeve gastrectomy , reporting a weight loss from 45.5  kg / m to 30.6  kg / m and 31.7  kg / m at 12 and 18 months , respectively , using a 48 fr calibration tube . a greek centre , at which a 38 fr bougie was used , reported a comparable weight loss from 45.3  kg / m to 30.5  kg / m for 246 patients undergoing isg . in a series of 163 patients undergoing isg using a 36 french calibration tube , weight loss from 45.9 kg / m to 33.1  kg / m and 31.6  kg / m was presented at 1- and 2-year followup . bougie size does not seem to have an impact on initial weight loss ; however , sleeve dilatation and a consequent regain of weight occur for larger bougies [ 18 , 25 ] . a diabetic metabolism with high insulin levels and thus inadequate glucose and lipid homoeostasis is expected to lead to poor weight loss after obesity surgery . this is supported by evidence found by caiazzo et al . , who reported an impaired weight loss for diabetic patients after laparoscopic gastric banding ( lagb ) at one - year followup . similar findings are presented by mathurin et al . , who reported a significantly lower weight loss for patients presenting with insulin resistance prior to obesity surgery ( laparoscopic gastric banding and bypass ) . however , these findings remain controversial , as others report no difference regarding weight loss in their subgroup analysis . our data suggest a significantly impaired weight loss for patients with elevated hba1c levels at baseline despite a good resolution of hba1c , suggesting elevated hb1ac level as a predictor for poor weight loss . however , weight loss is still highly significant in this group . comparing weight loss of patients diagnosed with nash during the operation to patients with normal liver histology , an impairment in loss of bmi is evident . this phenomenon can partly be explained by the impaired weight loss of diabetic patients ; however , only 14 of 87 patients with nash showed an hba1c above 6.5% . certainly , changes in adipokine profiling play a pivotal role in nash pathology . examined the effect of lagb on the histopathological features of nafld , performing two consecutive liver biopsies and determining plasma aminotransferase concentrations at a median followup time of 30 months . this group could show a significant correlation of aminotransferase concentrations and presence of nash at the first and second biopsies . an aminotransferase decrease of 38% could best and significantly predict the change in nash status . ulitzky et al . identified diabetes , alt , and triglyceride levels as independent risk factors for nash in multivariate analysis . in our cohort , we could show a strong correlation of preoperatively determined alt and hba1c levels with histologically confirmed nash . a limitation of our study is the lack of a second liver biopsy , which prevents clearly defining the effect of sleeve gastrectomy on liver histology . in the nash subgroup , however , we could show a significant reduction of triglyceride , hba1c , and alt levels , resulting in a significant reduction of nash incidence , when applying the ulitzky model . furthermore , patients diagnosed with nash presented with a 39% decrease in ast level . lacking a distinct algorithm , nash therapy is mainly based on the reduction of underlying risk factors . with obesity being the single most significant risk factor , weight loss surgery is widely discussed for the management of nash . a recently conducted cochrane research concerning this subject analyzed 21 independent studies . among the bariatric procedures used , the majority of the studies were conducted with roux - en - y gastric bypass ( 13 ) and adjustable gastric banding ( 6 ) . regarding histological outcomes , eighteen studies reported a significant improvement in the degree of steatosis and eleven studies reported an improvement in histological markers of inflammation . in 11 of 16 studies lfts improved in the course of followup , aggravation could not be observed . in concordance with the data presented above , . showed a 80.9% resolution of t2 dm after isg over a 3-year followup . in a series of 39 consecutive patients with preoperatively diagnosed t2 dm undergoing isg , vidal et al . presented a resolution of hba1c levels below 6.5% in 94.6% at 1-year followup . furthermore , they could show a 50% to 80% resolution of metabolic syndrome associated figures such as triglyceride and hdl levels , suggesting isg as a successful strategy for the management of different cardiovascular risk components of the metabolic syndrome . in our subgroup analysis of patients with elevated hba1c , the median hba1c level was within normal ranges for 87% of patients at 1- and 3-year followup . some believe that hormonal regulation plays a key role [ 20 , 34 ] . in this comparison of small bowel transit time from patients after isg to controls showed a significant reduction in transit time from 298.1  9.2 to 199  65.7 minutes . also , an increase on pyy can be seen after isg with possible amelioration of glucose control [ 37 , 38 ] . weight loss is greatest in the first months after operation , so it does not seem surprising to see rapid amelioration of t2 dm . in a recent , study performing lsg in nonmorbidly obese t2 dm patients resulted in a resolution of t2 dm in up to 50% 1 year after operation . the effect is related more to a decrease of insulin resistance because of calorie restriction and weight loss rather than to an increase of insulin secretion . besides weight loss , the amelioration of t2 dm most likely seems to create the condition for resolution of nash after isg . proposed that remaining insulin resistance is the main risk factor for nonresolution of nash after obesity surgery . furthermore , insulin sensitisers such as pioglitazone and rosiglitazone can be applied as medical treatment for nash [ 10 , 11 ] . the glp-1 agonist exenatide could be administered with success ; however , data are scarce [ 39 , 40 ] . changes in adipokine profiling add to this effect , especially given the fact that only 14 of 87 patients with nash had hba1c levels above 6.5% . for adiponectin , it was demonstrated that lower adiponectin levels are associated with increased severity of hepatic inflammation . a repletion of adiponectin in mice resulted in significant improvements in steatosis and inflammation [ 41 , 42 ] . for tnf- elevated plasma concentrations , as can be detected in obese patients , mediated hepatic injury by inhibition of mitochondrial electron transport and release of reactive oxygen species that stimulate lipid peroxidation . isg conducted in 236 patients resulted in a significant and sustained weight loss comparable to data presented by others . although a significant difference was seen between nash patients and patients with normal histology , nash patients showed a highly significant loss of body weight . for this subgroup , amelioration of hba1c levels and equally important amelioration of liver histology could be demonstrated . isg can be successfully performed in nash patients and , as a fairly easy and safe bariatric intervention to conduct , it can be particularly recommended for this subgroup .
background . 
 nonalcoholic fatty liver disease is present in up to 85% of adipose patients and may proceed to nonalcoholic steatohepatitis ( nash ) . with insulin resistance and obesity being the main risk factors for nash , the effect of isolated sleeve gastrectomy ( isg ) on these parameters was examined . methods . 
 236 patients underwent isg with intraoperative liver biopsy from december 2002 to september 2009 . besides demographic data , pre - operative weight / bmi , hba1c , ast , alt , triglycerides , hdl and ldl levels were determined . 
 results . 
 a significant correlation of nash with higher hba1c , ast and alt and lower levels for hdl was observed ( p < .05 , < .0001 , < .0001 , < .01 , resp . ) . 
 overall bmi decreased from 45.0  6.8 to 29.7  6.5 and 31.6  4.4 kg / m2 at 1 and 3 years . 
 an impaired weight loss was demonstrated for patients with nash and patients with elevated hba1c ( plateau 28.08 kg / m2 versus 29.79 kg / m2 and 32.30 kg / m2 versus 28.79 kg / m2 , resp . ) . regarding nash , a significant improvement of ast , alt , 
 triglyceride and hdl levels was shown ( p < .0001 for all ) . 
 a resolution of elevated hba1c was observed in 21 of 23 patients . 
 summary . 
 nash patients showed a significant loss of body weight and amelioration of nash status . 
 isg can be successfully performed in these patients and should be recommended for this subgroup .