Bariatric surgery and nonalcoholic fatty liver disease.

’Review article Bariatric surgery and nonalcoholic fatty liver disease Guy Bower, Thanos Athanasiou, Alberto M. Isla, Leanne Harling, Jia V. Li, Elaine Holmes, Evangelos Efthimiou, Ara Darzi and Hutan Ashrafian The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity-associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight-independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease. Eur J Gastroenterol Hepatol 27:755–768 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

The global epidemic of obesity is an escalating public health concern that places substantial pressure on healthcare systems and is a significant burden on national health expenditure [1–3]. The WHO defines obesity as a BMI [BMI: mass (regulation of energy metabolism)/height2 (m2)] of 30 kg/m2 or higher and overweight as a BMI of 25–29.9 kg/m2. It estimates that the incidence of obesity has almost doubled over the past two decades and that ∼ 2.8 million people die annually as a result of being overweight or obese. This results from an estimated prevalence of over 1.4 billion overweight adults and over 500 million obese individuals in 2008 [4]. It is estimated that this trend will continue to rise, such that by 2030 there will be over 2 billion overweight and over 1 billion obese adults worldwide [5]. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of conditions in which hepatic fat accumulation leads to chronic liver disease ranging from simple steatosis to steatohepatitis (NASH) and nonalcoholic cirrhosis. The global prevalence of NAFLD is also rising, particularly in western nations. The prevalence of NAFLD ranges from 2 to 44% in the general European population (including obese children) and from 42.6 to 69.5% among patients European Journal of Gastroenterology & Hepatology 2015, 27:755–768 Keywords: bariatric surgery, metabolic surgery, nonalcoholic fatty liver disease Department of Surgery and Cancer, Imperial College London, Imperial College Healthcare NHS Trust at St Mary’s Hospital, London, UK Correspondence to Hutan Ashrafian, MRCS, PhD, Department of Surgery and Cancer, Imperial College London, 10th Floor, Queen Elizabeth the Queen Mother (QEQM) Building, Imperial College Healthcare NHS Trust at St Mary’s Hospital, Praed Street, London W2 1NY, UK Tel: + 44 20 7886 7651; fax: + 44 20 7886 6309; e-mail: h.ashrafi[email protected] Received 28 December 2014 Accepted 23 March 2015

suffering from type 2 diabetes mellitus [6]. According to the World Gastroenterology Organization, there are ∼ 6 million individual NASH sufferers in the USA and 600 000 individuals with NASH-related cirrhosis [7]. Obesity is associated with several systemic comorbidities including type 2 diabetes mellitus, insulin resistance, hypertension and dyslipidaemia. These conditions come together under the common definition of metabolic syndrome, which in turn has been associated with NAFLD. As a result, the increased global prevalence of NAFLD in both adults and children has been considered to derive from the global increase in obesity [8–10]. Bariatric surgery is currently the most successful modality to manage morbid obesity, offering consistent longterm weight loss and resolution of obesity-related comorbidities, and these procedures are increasingly common, with over 344 000 cases now being performed annually [11]. There are a number of types of procedures, but the most commonly performed are the Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy and the adjustable gastric band. Most can be performed laparoscopically, and the 30-day mortality is 0.3% and the 30-day morbidity is 4.7% [12]. Long-term follow-up of gastric bypass patients has found the all-cause mortality rate to be 40% less than that in nonsurgical patients, with death rates from cardiovascular disease, diabetes and cancer being significantly reduced in surgically treated patients [13]. A meta-analysis of bariatric surgical outcomes revealed that bariatric procedures achieved effective weight loss as well as resolution of diabetes, hyperlipidaemia and hypertension in the majority of patients [14]. It has been reported that only 5% of patients attending for bariatric surgery had a normal liver histology, and that 25% had NASH [15], although results from a multitude of studies have suggested that bariatric surgery is associated with significant improvements in liver histology [16]. In this review, we

0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

DOI: 10.1097/MEG.0000000000000375

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appraise the literature on the clinical benefits of bariatric surgery on obesity-related liver disease and the possible mechanisms of action that may offer a reduction in liver dysfunction. Clinical studies on bariatric surgery and nonalcoholic fatty liver disease

Metabolic surgery has been found to be associated with both significant improvement and resolution of steatosis and NAFLD in obese patients consistently across the literature (Table 1). These studies also suggest that these beneficial effects may be less pronounced in patients with hepatic fibrosis, whereas there is some evidence to suggest that metabolic procedures in fibrotic patients are associated with a worsening of liver disease [42,49]. The largest single study on the effects of metabolic procedures on NAFLD comes from the Swedish Obesity Study, an ongoing prospective study comparing outcomes in obese patients undergoing bariatric procedures with outcomes in those undergoing usual treatment (lifestyle weight-loss programmes). The study compared alanine transaminase (ALT) and aspartate aminotransferase (AST)

levels of 3570 patients before and 10 years after intervention and found that patients undergoing bariatric surgery had a greater reduction in enzyme levels than patients undergoing nonoperative management [17]. However, liver histology was not assessed and other studies have shown liver enzyme levels to be normal in patients with histological evidence of steatosis and NASH [33]. One of the largest single studies that used liver histology as a primary outcome measure found a significant improvement in NAFLD in obese patients undergoing bariatric procedures. A total of 381 patients with a BMI greater than 35 kg/m2 were followed up with repeat liver biopsies for up to 5 years following the procedure. It was found that the rate of steatosis had fallen from 32.8% before surgery to 8.8% after surgery, and there was a reduction in the rate of NASH from 27.4 to 14.2% [42]. The significant improvements in NAFLD following bariatric surgery are associated with both restrictive and bypass procedures. However, one study found that laparoscopic RYGB resulted in a greater reduction of NAFLD than adjustable gastric banding or sleeve gastrectomy [40]. Furthermore, a recent comparison of adjustable gastric band with RYGB reported that the

Table 1. Clinic studies on the effects of bariatric surgery on NAFLD Liver histology

Intervention Nonsurgical/gastric band/ VBG/GB Intragastric balloon Gastric band Gastric band Gastric band/BIB VGB Gastroplasty Gastroplasty Gastroplasty/GB GB GB GB RYGB RYGB RYGB RYGB RYGB RYGB RYGB RYGB RYGB RYGB RYGB/LAGB RYGB/LAGB/SG RYGB/gastric band/SG RYGB/gastric band/BIB RYGB/gastric band/BDP-DS BPD-DS BPD-DS JIB Endoscopic DJBL Not documented

Number of participants

Follow-up (months)

3570

120

–

–

96 60 36 185 51

6 19.5–39.5 25 24 18

– ↓ ↓ ↓ ↓

10 69 15

41 12–32 12

78 16 7 26 21 84 39 18 16 19 16 90 91 756 70 20 381 116 78 104 31 17 40

– 17 12 13–19 12 12 6–41 24 15–32 13–32 0.3–1 12 2–61 36 6–24 8–22 60 11– 27 36 41 24–110 12 15–27

Liver enzymes

Steatosis Inflammation Fibrosis

Metabolic

AST

ALT

ALP

IR

Lipid

References

–

↓

↓

↓

–

–

Burza et al. [17]

– ↓ ↓ – ↓

– ↓ ↓ ↑ ↔

↓ ↓ ↓ – ↓

↓ ↓ ↓ ↓ ↓

– ↓ ↓ – ↓

↓ – ↓ ↓ ↓

– – ↓ ↓ ↓

– ↓ ↓

– ↑ ↔

– ↔ –

↓ – ↔

↓ – ↔

– – ↓

↓ – –

↓ – –

– ↓ ↓ ↓ ↓ – ↓ ↓ ↓ ↓ ↓ ↓ ↓ – ↓ ↓ ↓ ↓ ↓ – ↔ – –

– ↓ ↔ ↓ ↓ – ↓ ↓ ↓ ↓ ↓ ↓ – – ↓ ↓ ↓ ↓ ↓ – ↔ – –

↓ ↔ ↔ ↓ ↓ – ↓ ↓ ↔ ↓ ↓ ↓ ↓ – ↓ ↓ ↑ ↓ – ↑ ↔ – –

– – ↓ ↔ ↓ ↓ ↓ ↔ – ↔ ↓ ↓ – ↓ ↓ ↓ – – ↔ – ↔ ↓ ↓

– – ↓ ↔ ↔ ↓ ↓ ↔ – ↔ ↓ ↓ ↓ ↔ ↓ ↓ ↓ – ↔ – ↔ ↔ ↓

– – – ↔ – – – – – ↔ ↔ ↔ – ↔ – – – – – – – ↓ –

– – ↓ ↓ ↓ ↓ ↓ – ↓ ↓ ↓ ↓ – ↓ ↓ ↓ ↓ ↓ – – ↓ – ↓

– – ↓ ↓ ↓ – – ↓ ↓ ↓ ↓ ↓ – – ↓ ↓ ↓ ↓ – – ↓ – ↓

Ricci et al. [18]* Dixon et al. [19] Dixon et al. [20] Mathurin et al. [21] Stratopoulos et al. [22] Jaskiewicz et al. [23] Luyckx et al. [24] Ranlov and Hardt [25] Moretto et al. [26] Csendes et al. [27] Klein et al. [28] Vargas et al. [29] Tai et al. [30] Kakizaki et al. [31]** Liu et al. [32] Furuya et al. [33] de Almeida et al. [34] Barker et al. [35] Clark et al. [36] Mottin et al. [37] Silverman et al. [38] Xourafas et al. [39] Mattar et al. [40] Bell et al. [41] Mathurin et al. [42] Weiner [43] Keshishian et al. [44] Kral et al. [45] Meinhardt et al. [46] de Jonge et al. [47] de Andrade et al. [48]

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BIB, biliointestinal bypass; BPD-DS, biliopancreatic diversion with duodenal switch; DJBL, duodenal–jejunal bypass liner; GB, gastric bypass; IR, insulin resistance; JIB, jejunoileal bypass; LAGB, laparoscopic adjustable gastric band; RYGB, Rouxen-Y gastric bypass; SG, sleeve gastrectomy; VGB, vertical gastric band. *Liver assessed by ultrasound. **Liver assessed by computed tomography scanning.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Bariatric surgery and NAFLD Bower et al.

proportion of patients with NAFLD was lower among patients treated with RYGB than among those treated with adjustable gastric band for up to 5 years after surgery, and that this was despite patients in the RYGB group having more severe NAFLD preoperatively [50]. Bariatric surgery and hepatic fibrosis

Hepatic fibrosis is considered the end-stage of NAFLD: potentially irreversible damage to the hepatic tissue. Consequently, the potential for fibrosis to be arrested, or even to be resolved, with bariatric procedures is of interest. There are also concerns that bariatric procedures may be associated with a worsening of fibrosis as a result of rapid weight loss [51]. One study identified that, although fibrosis worsened in patients who had fibrosis at the time of operation, 95.7% of patients maintained a fibrosis score of no higher than 1 [42], suggesting little significant disease progression following surgery. Another study of 108 patients undergoing biliopancreatic diversion with duodenal switch found that severe fibrosis improved in 27% of patients. Furthermore, 11 patients with liver cirrhosis demonstrated improvement in their stage of liver disease up to 9 years after surgery [45]. Development of mild fibrosis in 40.4% of patients was reported, although subgroup analysis found a relationship between increased fibrosis and preoperative alcohol intake, which, among other factors, complicated the interpretation of results [45]. No study has directly compared surgical and nonsurgical management with regard to liver histology; however, histological improvement in steatosis can be obtained in obese patients who achieve a 5% weight loss with lifestyle interventions, whereas over 9% weight loss may be needed to improve histology in patient with NASH [52]. Weight loss in obese patients may also stop progression of hepatic fibrosis [53]. However, sustained weight loss through lifestyle measures and pharmacotherapy is difficult [54], and liver fibrosis may progress in up to one-third of patients with NAFLD within 4 years [55]. Data on the effects of bariatric procedures in patients with liver cirrhosis are limited [56]. There are concerns that operating on patients with advanced liver disease carries significant risk, and particularly rapid postoperative weight loss may well have an important role in the worsening of fibrosis [51]. The most recent summary of the available literature on bariatric surgery in cirrhosis patients found one perioperative death (from hepatorenal syndrome) out of 44 cases analysed [56]. Dallal et al. [57] have reported operating on 30 obese cirrhosis patients with no perioperative mortality or significant morbidity. Overall, out of 23 studies that analysed liver histology, 14 reported an improvement in fibrosis, six reported no significant change and three reported worsening of fibrosis (Table 1). Bariatric surgery, nonalcoholic fatty liver disease and insulin resistance

There is much published on the contributory effects of insulin resistance on the pathogenesis of NAFLD [58]. A number of studies have reported on the relationship between NAFLD and insulin resistance in obese patients

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undergoing bariatric procedures [21,42]. It is well documented that bariatric surgery can bring about resolution of insulin resistance and diabetes in obese patients [59], and a number of studies have reported improvements in metabolic profiles (hypertension, insulin resistance and lipid levels) to be associated with improvements in NAFLD [14]. Generally, patients who have resolution of insulin resistance have improved liver histology [21,42]. Moderate or severe steatosis is more frequently observed in patients who conserve a higher insulin resistance index after surgery than in patients who show improvements in their insulin resistance index [21]. One study found that histological changes (steatosis and hepatocyte ballooning) were more frequent in patients whose insulin resistance did not resolve postoperatively, and that a refractory insulin resistance independently predicted the persistence of NAFLD for up to 5 years after surgery [42]. Dixon et al. [20] found that patients with metabolic syndrome had worse liver histology preoperatively and a greater degree of improvement postoperatively. Indications for surgery in relation to nonalcoholic fatty liver disease

The level of obesity may have implications in the outcome of liver disease. A recent study comparing superobese adolescents (BMI > 50 kg/m2) and morbidly obese adolescents concluded that superobese patients had a poorer outcome with regard to metabolic abnormalities and NAFLD [60], suggesting that operations should be offered to patients before their BMI reaches that level. There are arguments for performing bariatric surgery on patients with a lower BMI (>30 kg/m2) in the presence of poorly controlled diabetes [61]. However, current guidelines have deemed it premature to offer bariatric surgery as a specific treatment for NAFLD [62]. The lack of large randomized trials that assess liver disease histology in patients undergoing bariatric procedures means that there is a lack of robust clinical data by which to justify such an indication [49]. Mechanisms of resolution following bariatric surgery

The pathological development of NAFLD, and its progression to NASH and fibrosis, has four key components (Fig. 1) related to obesity and the metabolic syndrome: (i) high dietary fats and carbohydrates, (ii) dysfunctional lipid metabolism leading to lipotoxicity, (iii) insulin resistance, and (iv) the chronic inflammatory response associated with obesity. The concept of lipotoxicity gives an account by which free fatty acids (FFAs) and their intermediates accumulate within hepatocytes, overburdening the usual lipid metabolism pathways and the endoplasmic reticulum stress response. This leads to increased oxidative stress, apoptosis and inflammation [58,63]. Whereas the excess triglyceride storage seen in steatosis is considered nontoxic (and may even have a protective effect [64]), an increase in the levels of FFAs and their metabolites generates lipotoxicity, the pathological stepping-stone to steatohepatitis and potentially fibrosis. FFAs also have cellular signalling functions, and their excess may be responsible for disordered signalling in important metabolic pathways [65].


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Vagal modulation Improved glucose + lipid sensing Hypothalamic stimulation of lipid accumulation

Obesity

Bariatric surgery

Beta oxidation

BRAVE effects

Adiponectin AdipoR2

Bile flow and absorption

Dietary fat

stimulation PPAR-α

Lipogenesis

AMPK activation

GLP-1 TGR5 FXR signalling

Peripheral lipolysis Lipotoxicity

GATA-4 TG absorption Lipogenesis

Insulin sensitivity

GLP-1 SIRT-1 cascade AMPK activation

HSC activation

FFA accumulation Oxidative and ER stress Inflammation Apoptosis Fibrosis

PPAR-α Incretin effect

Insulin resistance

FFA autophagy c-JNK activation

Inflammation

Gut microbe alteration PPAR-α

Inflammatory mediators (e.g. TNF-α, IL-6)

GLP-1 Intraluminal FFA synthesis

Resolution of NAFLD Fig. 1. Mechanisms of resolution of NAFLD following bariatric surgery. c-JNK, c-Jun N-terminal kinase; ER, endoplasmic reticulum; FFA, free fatty acid; FXR, farnesoid X; GLP-1, glucagon-like peptide 1; HSC, hepatic stellate cell; IL-6, interleukin-6; NAFLD, nonalcoholic fatty liver disease; PPAR-α, peroxisome proliferator-activated receptor alpha; TG, triglyceride; TNF-α, tumour necrosis factor-α; SIRT-1, Sirtuin-1.

The mechanisms leading to lipotoxicity are exacerbated by insulin resistance and by the subclinical systemic inflammatory response seen in obese individuals [58,63,64]. Bariatric procedures, particularly RYGB, have been shown to have a wide range of effects on metabolic function in obese patients. The BRAVE effect gives an account of how bypass surgery achieves many of these metabolic changes. Bile flow alteration, Restriction of stomach size, Altered flow of nutrients, Vagal manipulation and modulation of Enteric and adipose hormones combine to generate significant changes in metabolic function in obese patients [59]. These mechanisms have effects that are both weight-dependent and weight-independent. We aim to outline the mechanisms that are relevant to the improvements in NAFLD seen in obese patients following bariatric procedures. These are summarized in Fig. 1. Reduced dietary intake and malabsorption

Dietary overload with lipids is likely to cause accumulation of lipids within the liver [4]. Saturated fats and fructose, in particular, have been singled out as causing hepatic fat accumulation [66–68]. High levels of carbohydrates

cause increased fatty acid synthesis in hepatocytes and further contribute to the lipid burden [69]. Consequently, reduced consumption or absorption of dietary lipids, glucose and other carbohydrates may help reduce the accumulation of lipids within the liver. Although bypass procedures do not result in significant malabsorption of nutrients [15], studies on faecal fat content have suggested that there is a reduction in fat absorption following bypass operations [70]. Patients initially follow a strict diet after bariatric surgery and consequently consume fewer calories. Longer term caloric intake following RYGB is variable, but reductions have been reported [71]. A recent study compared dietary intake between patients undergoing gastric band and those undergoing RYGB and found that RYGB patients consumed proportionately less dietary fat, found sweet and high-fat food less palatable and had healthier eating behaviour than gastric band patients [72]. Altered neurohormonal responses to food after RYGB have also been studied in patients, and there is evidence that changes in gut-hormone release after the procedure may well be linked to changes in dietary habits [72].



Taken in combination, these effects of bariatric surgery may reduce hepatic lipid burden. However, simple dietary reductions in the intake of lipids, carbohydrates and total calories are far from the only factors by which bariatric procedures ameliorate NAFLD. Indeed, the changes in appetite and reduced food intake may result from metabolic changes, particularly the actions of gut hormones on the brain, which bariatric procedures induce in obese patients [72,73]. Lipid metabolism – gut hormones

The endocrine function of the gastrointestinal tract plays a role in hepatic lipid metabolism [74], and there has been much research on the effect of bariatric procedures on these hormones. A number of gut hormones have been described [glucagon-like peptide 1 (GLP-1), GLP-2, ghrelin, peptide YY (PYY), gastric inhibitory peptide (GIP) and oxyntomodulin], and their role in postsurgical weight loss and metabolic enhancement is increasingly well understood [59, 73]. The rearrangement of the gastrointestinal tract involved in bariatric procedures (particularly RYGB) seems to affect the circulating levels of a number of these hormones, which may well contribute to a reduction in dietary lipids and total calories through their anorexic effect on hypothalamic appetite centres [73], as well as to the regulation of energy metabolism [75]. From the point of view of improvements in NAFLD following bariatric surgery, GLP-1 has the clearest role in altering lipid metabolism. GLP-1 is secreted from the L-cells in the distal small intestine and proximal colon following ingestion of food and bile acids. It is most well known for its incretin (i.e. insulin sensitizing) effect [76,77]. Human studies have also shown that GLP-1 agonists improve hepatic steatosis in obese patients with type 2 diabetes [78]. Reductions in steatosis were not related to weight loss, but were related to improved glucose control, although interpretation of these results is complicated by patients being on other diabetic medications, such as metformin [78], which are known to ameliorate NAFLD [79]. GLP-1 has also been shown to have direct effect on hepatic lipid metabolism. Animal studies with GLP-1 analogues have demonstrated reduced hepatic lipid accumulation [80], reduced hepatic lipogenesis [81] and increased fatty acid β-oxidation [76]; thus GLP-1 helps the liver metabolize its lipid burden through mechanisms distinct from (but not completely unrelated to) those associated with insulin resistance. GLP-1 agonism has also been shown to reduce very-low-density lipoprotein production [82] and to have a beneficial effect on hepatic fibrosis in mice, which was independent of weight loss [83], suggesting that GLP-1 agonism may help reverse fibrotic change. The intracellular mechanisms by which GLP-1 affects lipid metabolism have been examined. Activation of the GLP-1 receptor on hepatocytes contributes towards the suppression of lipogenesis by increasing cAMP levels, which in turn leads to an increase in the phosphorylation of cAMP-activated protein kinase (AMPK), an important inhibitory factor of lipogenesis [81]. There is also evidence that GLP-1 activates the Sirtuin-1 cascade, which leads to further AMPK activation [84]. GLP-1 agonism in animal models has been associated with the downregulation of mRNA levels of acetyl-CoA carboxylase and fatty acid synthase, two genes that play a role in hepatic lipogenesis

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[85]. This was associated with reduced hepatic fat accumulation and increased insulin sensitivity [85]. GLP-1 agonism is also associated with increased peroxisome proliferator-activated receptor alpha (PPAR-α) expression in hepatocytes and may well lead to an increase in FFA βoxidation through this pathway [76]. GLP-1 may improve the ability of the endoplasmic reticular stress response to safely metabolize the excess FFAs, and increase fatty acid autophagy. Fatty acids constitute a high burden of unfolded proteins, which stimulate, and eventually overwhelm, the endoplasmic reticulum stress response (also known as the unfolded protein response), leading to hepatocellular damage and directing the cell cycle down the path of apoptosis [86,87]. Furthermore, high-fat diets in mice have been shown to reduce autophagy of lipids in the liver, impairing yet another means by which hepatocytes could otherwise safely process high levels of accumulated fatty acids [88,89]. GLP-1 agonism has been shown to increase the expression of glucose-regulated protein, 78 kDa, a key chaperone protein in the normal protein-folding mechanisms within the endoplasmic reticulum, and to reduce the levels of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein [86]. It was also shown to increase the rate of autophagosome formation as well as the levels of autophagy markers, although the mechanisms by which GLP-1 may effect these changes require further investigation [86]. The net result is an increase in the capacity of hepatocytes to safely metabolize FFAs, reducing apoptosis and cell damage. Bariatric surgery is known to effect GLP-1 secretion. Increased postprandial levels of GLP-1 are seen after RYGB, biliopancreatic diversion and sleeve gastrectomy [90,91] but are not seen in patients who achieve similar weight loss through diet alone [92], suggesting that surgical changes to the gastrointestinal tract anatomy have an effect on hormone release that is independent of weight loss. Higher levels of GLP-1 are seen after RYGB than after sleeve gastrectomy for up to 3 months postoperatively [93]. RYGB involves the formation of a biliopancreatic limb that allows bile acids, undiluted by ingested food, to pass into the jejunum proximal to the anastomosis of the Roux limb. It is thought that this increase in the concentration of bile acids in the proximal small bowel may stimulate increased secretion of GLP-1 [73,74]. There is also the hindgut hypothesis – that is, food that has bypassed the foregut has an enhanced stimulatory effect on hindgut hormone release when compared with the normal, presurgical anatomy [59]. Although this rearrangement is absent in sleeve gastrectomy, it has been postulated that the increased transit time of food through the gut seen after sleeve gastrectomy may explain the moderate postoperative rise in GLP-1 levels [73,94]. The effect of other gut hormones on NAFLD following bariatric surgery is less clear. Although a number of other hormones have been implicated in weight loss, studies have defined no clear role for them in lipid metabolism, nor have identified a distinct effect of bariatric surgery on their action or secretion [73,74]. For example, ghrelin (a gut hormone secreted from the stomach fundus) is known to increase hunger and have a variety of metabolic effects such as exacerbation of insulin resistance, increase in lipogenesis, reduction in lipolysis and anti-inflammatory actions [95]. Interestingly, the circulating levels of ghrelin


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are low in obese individuals [96], complicating our understanding of its role in appetite regulation in obese individuals. A number of studies have looked to define the role of ghrelin in surgically induced weight loss, but significant variation between high, low and unchanged levels following bariatric procedures have been reported [59,73]. Elucidating its role in NAFLD has been complicated by issues surrounding the assays used in the studies (ghrelin has several active forms, and different assays result in different forms being analysed) [73]. Human studies have found that higher levels of ghrelin were correlated with a low risk of developing NAFLD [97], whereas ghrelin infusions in NAFLD mice have demonstrated reduced inflammation, oxidative stress and hepatocyte apoptosis [98]. However, one study found that higher grades of fibrosis were associated with higher serum levels of ghrelin [99]. PYY and GIP may also play a role in improving NAFLD following surgery. PYY is cosecreted from L-cells with GLP-1 in response to ingested food and bile [73]. Like GLP-1, increases in the levels of PYY are seen after bariatric surgery (with the exception of gastric banding [100]), to a degree that is not seen in patients with nonsurgical weight loss [101]. Although increased PYY secretion may help ameliorate NAFLD through its anorexic effects [73], no clear role for it in lipid metabolism has been defined [74]. High levels of GIP, a gut hormone secreted from K-cells in the proximal intestine in response to glucose, are seen in obese individuals and are associated with a blunting of the incretin effect of K-cells [102]. It has also been shown to have effects on lipid metabolism in rodent adipocytes, promoting lipid storage through stimulating increased FFA uptake, synthesis and storage [74], whereas the combination of GIP infusion, hyperglycaemia and hyperinsulinaemia in humans may increase FFA re-esterfication [103]. However, therapeutic experiments with GIP have not shown an obvious role for it in NAFLD [74], and the effect of bariatric surgery on GIP is unclear [104]. Biliopancreatic diversion in obese diabetic patients is associated with lower postprandial GIP levels, but a similar reduction is not seen in nondiabetic individuals [105]. This may be explained by the improvement in glucose levels in diabetic patients after surgery, which would reduce the stimulation of GIP release [73,105]. Bypassing the proximal intestine may result in reduced secretion of GIP, as food avoids the section of the gut most responsible for GIP release. However, studies have reported both increases and decreases in GIP following RYGB and, although a reduction in GIP may have some weightdependent benefit in steatosis through reduced fat accumulation [73], it currently has no clear role in improving NAFLD following bariatric procedures. Lipid metabolism – bile acids

Bile acids have been shown to stimulate GLP-1 release through stimulation of L-cells (as detailed above), and there are a number of other receptors within the hepatobiliary system that bile acids act on. Of relevance to bariatric procedures – particularly bypass operations that involve insertion of the ileum into the proximal small bowel, thus increasing the concentration of bile acids to

which it is exposed – is TGR5, a G-linked plasma membrane bile acid receptor present on Kupffer cells (as well as other hepatobiliary cell types) [106]. Stimulation of this receptor by bile acid leads to a reduction in the release of proinflammatory cytokines, including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and nuclear factor-κB65 (NF-κB65) [106], all which have been implicated in NASH. Rats that have undergone ileal interposition surgery (a procedure that involves resecting the distal ileum and repositioning it in the proximal jejunum) have increased levels of serum bile acids and improved metabolic parameters [107]. This suggests that ileal interposition creates a ‘short-circuit’ in the enterohepatic biliary cycle, which increases bile acid reabsorption and consequently increases the plasma levels of bile acids [107]. High levels of bile acids have been demonstrated in animal models [108] and humans after bariatric surgery and may contribute to improvements in lipid and glucose metabolism [109]. Interestingly, histological analysis of the transposed ileum in rats demonstrated ‘selective jejunization’: it had longer villi length, increased number of GLP-1-secreting L-cells and more active bile salt reabsorption transporters [107]. Increasing data on the role of bile acids and their receptors in mediating the beneficial effects of bariatric surgery have been obtained from a rodent model of sleeve gastrectomy [110]. Here, knockout mice for the farnesoid X bile acid receptor (a key participant in lipid and glucose metabolism) identified the contributory role of farnesoid X in maintaining weight loss and glycaemic control after this bariatric procedure. Lipid metabolism – transcription factor GATA-4

Another finding of the ileal interposition study was that the expression of the intestinal transcription factor GATA-4 was increased on the interposed ileum when compared with the nontransposed ileum, but it was less when compared with that on the native jejunum [107]. Observations from GATA-4-knockout mice have implicated lower levels of GATA-4 expression as having a role in reduced triglyceride absorption and reduced de-novo hepatic lipogenesis [111]. These mice also showed a reduction in hepatostellate cell activation and in inflammatory or fibrotic markers, implicating GATA-4 in ameliorating progression to fibrotic liver disease [111]. Consequently, replacement of the jejunum, high in GATA-4 concentration, with the ileum, with a lower GATA-4 concentration, could lead to a functional reduction in the total GATA-4 expression, which helps reduce hepatic lipogenesis, inflammation and fibrosis. Lipid metabolism – adipocytokines

The metabolic function of adipocytes is deranged in obesity, particularly in the presence of insulin resistance, and is thought to contribute to NAFLD by increasing the flux of serum lipids through the liver. A number of adipocytederived hormones and cytokines (adipocytokines) have been identified and shown to have a variety of systemic effects, including regulation of food intake, insulin sensitivity, nutrient metabolism and inflammation [112]. With regard to the effect of bariatric surgery on NAFLD,



adiponectin and inflammatory mediators secreted by adipose tissue (e.g. TNF-α and IL-6) are of particular interest. Adiponectin levels are low in NAFLD and obese patients, and lower levels have been shown to be correlated with worse disease [113–115]. Circulating levels are inversely associated with visceral body fat, whereas increased levels are associated with a lower risk for type 2 diabetes [59]. Patients with NASH have 50% lower adiponectin levels compared with healthy individuals, and low levels are associated with worse degrees of inflammation [116]. Adiponectin is thought to have a direct antisteatotic effect on the liver, to improve insulin sensitivity and to reduce inflammation, all of which are likely to contribute to its role in ameliorating NAFLD. The higher molecular weight form of adiponectin has been shown to decrease steatosis through activation of AMPK and through increased PPAR-α ligand activity [117], thus increasing fatty acid oxidation. Adiponectin levels have been shown to increase following RYGB [118,119], as well as in patients with weight loss from caloric restriction [120], suggesting that the mechanism by which adiponectin levels increase after surgery is weight-dependent. However, other studies have found no increase in adiponectin levels following weight loss from dietary interventions [121], maintaining the possibility that there are metabolic changes following surgery that have an effect on adiponectin independent of weight loss. The role of leptin and resistin in NAFLD following bariatric surgery is less clear [59], and the roles of TNF-α and IL-6 have been discussed below. Lipid metabolism – gut microbia

The role of gut microbia in fat metabolism has been explored, and particular species of flora are thought to increase lipid absorption and expression of prolipogenic factors [122,123]. The use of probiotics in mice with NAFLD has shown a reduction in hepatic fat content through a reduction in cholesterol synthesis (through inhibition of SREBP-2) and an increase in fatty acid oxidation (through increased expression of PPAR-α) [123]. The authors speculated that increased GLP-1 release provoked by the probiotic bacteria may have contributed to the increased PPAR-α expression seen in the study subjects [123]. Application of our animal model of RYGB [124] identified that the most pronounced weighted metabolic shift in systemic metabolism after bariatric surgery was the modulation of microbial metabolites [108]. Studies on the differences in the composition of gut flora between lean, obese and post-RYGB patients found that obese patients had much higher levels of methanogenic bacteria compared with the other groups. These bacteria are responsible for the increase in intraluminal short-chain fatty-acid synthesis, with a consequent increase in gut absorption [125]. It is postulated that the gut rearrangement in RYGB creates a more acidic and oxygen-rich environment that is less favourable for methanogens and more favourable for other bacteria, which make up the majority of colonizing species after RYGB, thus reducing bacteria-led intraluminal short-chain fatty-acid synthesis [125]. We demonstrated a shift in bacterial composition toward a profound

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increase in Proteobacterium spp. and a decrease in Firmicutes and Bacteroidetes. This was associated with a significant change in the levels of systemic energetic metabolites and a move in metabolism toward gut digestive putrefaction and altered systemic bile concentrations. These gut flora changes reveal the importance of the microbial–mammalian dialogue in postbariatric physiology [108] and may represent the fulfilment of the BRAVE effects of bariatric surgery. Lipid metabolism – neuronal mechanisms

The role of the vagus nerve and central nervous system pathways in food intake, weight gain and glucose control has been the subject of controversy. This includes the role of the vagus nerve in the gut–brain–liver axis [126] to concomitantly regulate appetite and foregut-controlled metabolism. In RYGB, there is denervation of the bypassed stomach, but vagal supply to the gastric pouch, intestines, liver and hepatic portal vein should remain intact [127]. There is evidence that this vagal dissection contributes to early weight loss and may improve glucose homoeostasis [59,128]; thus, the vagus nerve contributes to the BRAVE effects of bariatric surgery. There may also be a role of the central nervous system and vagus nerve in lipid metabolism and NAFLD. Mice deficient in the hypothalamic neuropeptide melaninconcentrating hormone are protected against obesity, hepatosteatosis and insulin resistance [129]. Stimulation of melanin-concentrating hormone receptors in mice with an intact vagal nerve was shown to increase hepatic lipid accumulation through the parasympathetic nervous system pathways. However, mice that underwent vagotomy showed lower serum FFA levels and hepatic FFA levels compared with sham-operated mice [129], implicating hypothalamic stimulation of vagal efferents as playing a role in hepatic lipid metabolism, as well as in glucose regulation. However, understanding of the role of the vagus nerve in the context of bypass procedures is incomplete. Sensing of portal vein glucose concentration by vagal afferents, effected by intestinal gluconeogenesis, has been postulated as one method by which the gut–brain–liver axis works to control glucose homoeostasis [130], and the modulation of intestinal gluconeogenesis and portal vein sensing has been put forward as one means by which RYGB improves glucose tolerance [131]. However, dissection of the common hepatic branch of the vagus nerve in rats undergoing RYGB made no difference to weight loss, food-intake or energy expenditure when compared with RYGB rats with an intact common hepatic branch [127]. This branch of the vagus nerve innervates the liver, hepatic portal vein and proximal duodenum, and has been shown to have roles in sensing dietary lipids [132] and in glucose homoeostasis [127]. Conflicting results in this area reveal that, although vagal effects contribute to postbariatric effects, their exact effect on NAFLD and postoperative physiology requires further clarification. Insulin resistance

There is a high incidence of insulin resistance among obese patients with NAFLD [79], and NAFLD is often considered the hepatic component of the metabolic syndrome [133,134].


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NAFLD patients have both hepatic and peripheral insulin resistance [79]. Hepatic insulin resistance results in increased de-novo lipogenesis, creating further excess levels of hepatocyte triglycerides and FFAs [74]. Peripheral insulin resistance exacerbates FFA accumulation by blunting the insulinmediated inhibition of lipolysis in adipocytes, consequently leading to an increase in the circulating levels of FFAs passing through the liver. FFAs and their metabolites are also thought to interfere with insulin signalling, further suppressing insulin’s antilipolytic effects [135]. Finally, hepatic glucose release is increased as a consequence of disrupted insulin signalling. The resulting hyperglycaemia further impairs lipid metabolism by stimulating lipogenesis through activation of the carbohydrate response binding protein [136]. The extent to which insulin resistance is a cause or consequence of NAFLD currently remains unanswered. The ability of bariatric procedures to improve insulin sensitivity is well documented [14], and both restrictive and bypass procedures are widely accepted as being able to rapidly resolve type 2 diabetes in obese patients. The BRAVE effect and the mechanisms by which it achieves improved insulin sensitivity have been reviewed elsewhere [59]. It is outside the scope of our paper to explain each in detail. However, improved insulin sensitivity is closely associated with improvement in NAFLD. Clinical studies have reported associations between improved liver histology and improved metabolic parameters, particularly serum lipid levels and insulin resistance, after bariatric surgery [20,40]. Other studies have shown insulin resistance persisting beyond surgery to be a strong predictor of nonresolving NAFLD [42]. Some of the mechanisms through which bariatric procedures alter fat metabolism also play a role in improved insulin sensitivity. Decreased expression of GLP-1 receptors in obese individuals is likely to contribute to hepatic insulin resistance [76]. A study of GLP-1 agonists in patients with hepatic steatosis and type 2 diabetes found that the marked improvements in steatosis were associated with improved HbA1c levels [78]. GLP-1 receptors found in the brain and may also have a role in improving hepatic insulin resistance. Their stimulation has been found to be associated with increased insulin secretion and insulin signalling within the livers of mice receiving GLP-1 cerebrospinal infusions [137]. GLP-1 is known to improve insulin sensitivity, and its levels increase following bariatric procedures [73]. The direct effects of GLP-1 on hepatic steatosis have been discussed above. To what extent the hepatocyte lipid content is reduced by insulin sensitivity-independent mechanisms compared with insulin sensitivity-dependent mechanisms is not clear. Increased levels of adiponectin following bariatric surgery are also likely to contribute towards the improvement in insulin resistance. Activation of the AdipoR2 receptor by adiponectin has been shown to increase insulin sensitivity [117] and may contribute towards an improvement in steatosis through this mechanism, as well as towards its more direct antisteatotic effects. Retinal-binding protein 4 (RBP4) and fetuin-A are two further insulin-blunting mediators that have been shown to be reduced following bariatric procedures [138–140]. RBP4 is a vitamin A transport protein secreted by adipocytes and hepatocytes that has been shown to induce insulin resistance in muscle, liver and fat [141]. Although

its role in NAFLD is not clear, increased serum concentrations are thought to be related to excess hepatic fat accumulation [142], and obese individuals with NAFLD have higher circulating levels compared with those with normal liver histology [143]. It is not clear whether obesity alone is associated with high levels of RBP4, and its role in improved insulin sensitivity in obese diabetic patients following weight loss is a subject of debate [140]. Postoperative reductions in RPB4 levels have been reported inconsistently [140] and seem to be related to weight loss rather than to weight-independent mechanisms, with similar reductions seen in patients achieving significant dietary weight loss [139]. Interestingly, bypass procedures are associated with a greater reduction in RBP4 levels compared with sleeve gastrectomy, with authors proposing reduced duodenal absorption of retinol as causing downregulation of RBP receptor expression [139]. Fetuin-A is a protein secreted by hepatocytes that inhibits the tyrosine kinase insulin receptor activity on skeletal muscles and the liver [144]. It is elevated in the livers of obese patients with NAFLD and is thought to have an inhibitory effect on adiponectin secretion, which may contribute to its insulin desensitizing role [144,145]. The effect of bariatric surgery on the circulating levels of fetuin-A remains to be fully elucidated. A fall in levels has been reported in the immediate postoperative period [139] and up to 16 months after surgery [146]. However, one study reported a rise in serum fetuin-A levels in patients with NASH 4 weeks postoperatively [145], which returned to preoperative levels at 6 months. Adiponectin levels were increased during the same time period, challenging the notion it has a straightforward inhibitory relationship with fetuin-A. Inflammatory modulation

Obesity is associated with a systemic chronic low-grade inflammatory response, and a number of cytokines have been identified as playing a role in the development of hepatic inflammation – an important pathological step from simple steatosis towards NASH and potentially fibrosis. The chronic inflammatory state in obesity also contributes to blunted insulin sensitivity [147–150] and is thought to have a direct effect on hepatocyte lipid metabolism, as some cytokines released from immune cells have been shown to stimulate lipogenesis [151]. The inflammatory response within the liver is stimulated by increased FFA levels and oxidative stress. FFAs have been shown to activate the NF-κB pathway in the liver, which results in cytokine release (particularly TNF-α, IL-6 and IL-1β) and subclinical hepatic inflammation [152]. In addition to hepatic inflammation, excess adipose tissue plays an important proinflammatory role, with increased infiltration of inflammatory cells into adipose tissue and additional secretion of inflammatory mediators from adipocytes [153,154]. Animal studies have shown how increased secretion of monocyte chemoattractant protein-1 from adipocytes under a high-fat diet leads to increased monocyte infiltration of adipose tissue, priming it as a site for increased proinflammatory activity [155]. TNF-α is secreted by adipocytes, hepatocytes and Kupffer cells [154] and has been shown to induce insulin resistance and inflammation in humans [156]. High levels



of serum TNF-α are seen in patients with obesity and insulin resistance [154,157], and TNF-α levels are positively correlated with the degree of liver fibrosis in NAFLD [158]. Animal models have shown that treatment with anti-TNF-α agents can reduce NASH and fibrosis [159], suggesting its role in advancing NAFLD towards the fibrotic endpoint. GLP-1 is also likely to have a role in reducing inflammation, as it has been shown that GLP-1 agonism is associated with a reduction in TNF-α mRNA levels in mice models treated with liraglutide [85]. However, other studies have failed to find similar results and, hence, question the extent of the role of TNF-α in NAFLD [154]. IL-6 has a complex role in the development of NAFLD and insulin resistance. It may have a paradoxical role, sensitizing the liver to injury, at the same time having a protective effect [154]. IL-6 is thought to be secreted by adipose tissue in obese individuals [160], and serum levels fall by 43% following RYGB. This reduction is associated with improved insulin sensitivity [160]. Furthermore, circulating levels are higher in patients with NAFLD, and increased hepatocyte expression of IL-6 is seen in the livers of patients with NAFLD [161]. IL-1α is another potentially important cytokine in NAFLD. IL-1α-knockout mice have show significant resistance to the development of NASH despite substantial hepatic lipid accumulation and high serum lipid levels, highlighting the role of IL-1α in the initiation of hepatic inflammation in steatosis [162]. The effect of bariatric surgery on IL-1α has not been widely studied. A statistically significant reduction has been reported on diet-led weight loss in morbidly obese patients [163], although this small study did not find a statistically significant reduction in IL-1α levels in patients undergoing bariatric surgery. Fetuin-A is known to have a proinflammatory effect [144] and high levels are associated with hepatic steatosis, insulin resistance and the subclinical inflammatory state of the metabolic syndrome [164,165]. As mentioned above, increased levels of fetuin-A have been reported following bariatric surgery in patients with NASH. Interestingly, this was associated with a reduction in markers of hepatocyte apoptosis, suggesting reduced inflammation-mediated cell damage despite the rise in fetuin-A levels [145]. Its proinflammatory role in NAFLD is further complicated by its ability to inhibit transforming growth factor-β (a known profibrotic mediator in hepatic fibrosis), suggesting a potentially protective role against fibrotic change [166]. Interestingly, a negative correlation between fetuin-A and fibrosis has been reported [145,167]. Adiponectin has been shown to have an antiinflammatory role through suppressed activation of Kupffer cells and hepatic stellate cells [154], and there is evidence that it inhibits the expression of TNF-α [168]. Its effects on hepatic stellate cells are of particular importance, as these cells are responsible for instigating fibrotic change in the liver [168], implicating adiponectin as a potentially important factor in stopping progression to fibrosis. The suppression of adiponectin by fetuin-A may have implications in the context of inflammatory modulation [144]. However, as discussed above, the concurrent increase in adiponectin and fetuin-A seen in the early postoperative period in NASH patients does not sit easily with a straightforward suppressing effect of fetuin-A

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on adiponectin following bariatric surgery. It has been proposed that adiponectin may be suppressed in obese individuals by TNF-α release stimulated by fetuin-A [144]. However, the potential suppressing effect of adiponectin on TNF-α discussed above serves to highlight the complexity of the inflammatory dynamic present in obese and postbariatric surgery participants. Studies on the role of c-Jun N-terminal kinase (c-JNK) in the development of NAFLD have shown it to be a potential common intracellular pathway for a number of the prosteatotic and proinflammatory factors discussed above. TNF-α, IL-6, reactive oxygen species, increased serum fatty acid levels and insulin resistance all increase the activation of c-JNK, and increased c-JNK activation is associated with worsening of steatosis and hepatocellular injury [169]. GLP-1 agonism in mice models with NAFLD has been shown to inhibit c-JNK signalling and reduce hepatic lipid accumulation [85]. These chronic inflammatory processes may also have implications in the understanding of the increased cardiovascular risk in NAFLD patients and the beneficial effects of bariatric surgery on mortality rates. For example, serum amyloid A (SAA) is an acute phase protein involved in atherosclerotic plaques and associated with increased cardiovascular risk [170]. Circulating levels of SAA are elevated in obese individuals (as a consequence of increased production in excess adipose tissue) and are seen to reduce following RYGB [170], suggesting a link between reduced inflammation and reduced cardiovascular risk. Interestingly NAFLD is emerging as an independent risk factor for cardiovascular disease (CVD), and studies have shown it to be associated with increased subclinical atherosclerosis [171]. The association between CVD and NAFLD is important, as obese individuals with NAFLD are more likely to die from myocardial infarction than from liver disease [171]. Given that a number of the mechanisms of NAFLD outlined above (high IL-6 and TNF-α, insulin resistance, hypoadiponectinaemia and increased oxidative stress) play a role in atherosclerosis, there is a strong case for the metabolic and inflammatory dysfunction associated with obesity being involved in both NAFLD and CVD [171]. Interestingly, the severity of atherosclerosis seems to be proportional to the severity of NASH (as opposed to simple steatosis), and a possible role for NASH as an augmenting factor in atherosclerotic acceleration has been suggested, particularly with regard to the increased activation of the NF-κB pathway seen in the livers of NASH patients [171,172]. Overall, bariatric surgery results in decreased oxidative stress and attenuated levels of systemic inflammatory markers such as IL-6, C-reactive protein, sialic acid, plasminogen activator inhibitor-1, malondialdehyde, SAA and von Willebrand factor [119,170,173–176]. This widespread anti-inflammatory effect is likely to contribute not only to the improvements in NASH seen after bariatric surgery (and the reduced risk of disease progression), but also to many of the other beneficial effects seen after bariatric surgery, such as the reduction in cardiovascular risk and overall mortality. The reduction in inflammatory markers is more pronounced in patients with normal glucose tolerance when compared with insulin-resistant patients [119,175], highlighting the


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synergistic relationship between fat metabolism, insulin resistance and inflammation in NAFLD.

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Conclusion

Bariatric surgery has been successfully introduced to demonstrate consistent benefit in the management of morbid obesity and its comorbidities. There is now extensive cohort study data supporting the beneficial role of bariatric procedures in preventing and resolving NAFLD. The mechanisms through which bariatric surgery may improve NAFLD can be appraised through improved lipid metabolism, improved insulin sensitivity and decreased lipid load (with weight loss). These pathways are intimately connected, where key intermediary contributors such as GLP-1 demonstrate multiple roles in their mechanistic pathways. The reduction in chronic inflammation also directly contributes to the beneficial effects of these processes on NAFLD. Nevertheless clinical data on the effects of bariatric procedures on the various stages of NAFLD remain incomplete and heterogeneous, which limits the identification of distinct treatment targets at individual disease stages and grades. The future of this field will require further integration of higher-level clinical trials and mechanistic data derived from the systemic appraisal of the systems biology of NAFLD and its modulation through bariatric surgery. Coalescing these elements by adhering to the principles of personalized medicine for patients with obesity-associated liver disease can contribute to the multifaceted resolution of this disorder through the next generation of bariatric procedures to diminish the profound morbidity and mortality associated with it.

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Acknowledgements Conflicts of interest

There are no conflicts of interest.

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Nonalcoholic fatty liver disease and bariatric surgery in adolescents.

Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis.

The effect of bariatric surgeries on nonalcoholic fatty liver disease.

High Prevalence of Nonalcoholic Fatty Liver Disease in Adolescents Undergoing Bariatric Surgery.

Bariatric surgery for nonalcoholic fatty liver disease in adolescents with severe obesity.

Nonalcoholic fatty liver disease and cardiovascular disease.

Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients.

Nonalcoholic fatty liver disease and hepatocellular carcinoma.

Nonalcoholic fatty liver disease and hepatocellular carcinoma.

Probiotics and Nonalcoholic Fatty liver Disease.

Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease.

CKD and nonalcoholic fatty liver disease.

Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Herbal medicines and nonalcoholic fatty liver disease.

Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: a Systematic Review of Liver Biochemistry and Histology.

Pharmacotherapy for Nonalcoholic Fatty Liver Disease.

Biomarkers in nonalcoholic fatty liver disease.

Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Obesity-associated nonalcoholic fatty liver disease.

nonalcoholic steatohepatitis.

nonalcoholic steatohepatitis.

Nonmedicinal interventions in nonalcoholic fatty liver disease.

Endocrine causes of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease: Diagnostic biomarkers.