Seminars in Pediatric Surgery 23 (2014) 49–57

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Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg

Nonalcoholic fatty liver disease and bariatric surgery in adolescents AiXuan Holterman, MDa,b,n, Juan Gurria, MDa, Smita Tanpure, MSa,b, Nerina DiSomma, BAa,b a b

Department of Surgery, University of Illinois College of Medicine, Peoria, Illinois Pediatric Surgery, Children's Hospital of Illinois, University of Illinois College of Medicine, Peoria, Illinois

a r t i c l e in fo

Keywords: Nonalcoholic fatty liver disease Metabolic dysfunction Adolescent morbid obesity

a b s t r a c t Obesity is a multi-organ system disease with underlying insulin resistance and systemic chronic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the underlying metabolic dysfunction. This review provides a highlight of the current understanding of NAFLD pathogenesis and disease characteristics, with updates on the challenges of NAFLD management in obese and severely obese (SO) patients and recommendations for the pediatric surgeons' role in the care of SO adolescents. Published by Elsevier Inc.

Introduction As the epidemic of obesity rises, obesity-related nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a global health burden. Yet, the hepatic and extra-hepatic morbidities of NAFLD are underappreciated, underdiagnosed, and potentially undermanaged. Our understanding of this disease entity is still evolving and relies on publications from gastroenterology/hepatology practices at specialized centers that focus on overweight and obese patients. For the severely obese (SO) NAFLD patients, who are at the extreme end of the obesity spectrum, and in whom effective non-surgical therapy for weight loss and NAFLD is non-existent, the information is scant. Important gaps remain in the current overall approach to the screening, diagnosis, management, and follow-up of NAFLD patients.

Definition NAFLD is a spectrum of liver pathologies seen in patients with underlying insulin resistance (IR), dyslipidemia, hypertension, and, primarily, obesity. It ranges from nonalcoholic fatty liver (NAFL) or simple benign steatosis, defined as hepatic fat infiltration of 4 5% of the liver, to the inflammatory form of NAFLD known as nonalcoholic steatohepatitis (NASH) characterized by steatosis, inflammation, and hepatocyte ballooning, with or without fibrosis and necrosis.1 Other causes of fatty liver have to be ruled out to confirm the diagnosis of NASH. They include viral infections, drugs, toxins, autoimmune, metabolic diseases, such as cystic fibrosis or n

Correspondence to: 420 NE Glen Oak, Suite 201, Peoria, Illinois 61603. E-mail address: [email protected] (A. Holterman).

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Wilson's disease, and significant ethanol (EtOH) intake, which have histology that can be indistinguishable from NASH. There are 3 main systems used to describe NAFLD, the Brunt score,2 the NASH clinical research network activity score (NAS),3 and the pediatric NAFLD histological score (PNHS),4 all of which require liver biopsy. The definition of NAFLD histology has not been well characterized or consistent between publications, with these methods having been used for different applications. For instance, the NAS classification relies on individual histological scores of steatosis, inflammation, and hepatocyte ballooning as a system to report follow-up liver biopsies in longitudinal trials. Yet, it has been incorrectly applied to identify NASH based on a “threshold” value of NAS.5 The American Association for the Study of Liver Disease (AASLD) recently recommended a unified classification system of (1) NAFL or simple steatosis/not NASH (fatty liver with minimal hepatic inflammation), (2) definitive NASH (lobular and/or portal inflammation and hepatocellular ballooning with or without fibrosis), and (3) “borderline” NASH. NASH is thought to be a transitional stage from NAFL to hepatic fibrosis1 with inflammation as a predictor of disease progression to hepatic fibrosis.6 This is clinically limiting in that although hepatic fibrosis is the best prognosticator of end-stage liver disease,7,8 it is not part of the operational definition for NASH. The other limitation is the peculiarity of pediatric NAFLD histopathology, which has not been addressed in many publications, until the pediatric NAFLD histological score (PNHS) recently incorporated histologic scores of portal inflammation in its own classification.

Clinical significance NAFLD, specifically NASH, is currently the primary cause of liver function abnormalities and chronic liver disease in adults7 and in

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children.9 It is predicted to be the most common indication for liver transplantation10 in the next 10 years. Except for rare reports of progression,11,12 longitudinal studies have shown that pure steatosis (NAFL, steatosis/no NASH) is not associated with liverrelated mortality.13–15 In contrast, NASH patients, especially patients with insulin resistance and obesity, are likely to have aggressive liver disease progression and liver-related complications.13,16,17 The risk for progression to cirrhosis is 20% in 10 years, with a 12% risk for liver-related death and for hepatocellular carcinoma,18 especially in patients with advanced fibrosis/cirrhosis.19–22 NASH indeed is thought to be an underlying cause for cases previously labeled as idiopathic or cryptogenic cirrhosis.18 Children have similar risks for progression from NASH to decompensated end-stage liver disease requiring liver transplantation,23,24 making pediatric NASH an urgent public health issue. Patients with NAFL or NASH have additional morbidities, such as higher hepatic complications following liver resection.25 NAFLD patients have increased overall risk of death relative to the general population,26 with cardiovascular disease as the most common cause of death.13 The cardiac risks are predictable considering the powerful association of NAFLD with metabolic syndrome (MS).26,27 MS [presence of 3 components among severe obesity; visceral obesity by waist circumference; type 2 diabetes mellitus (T2DM); IR measured by fasting serum insulin and glucose, hypertension, and dyslipidemia using guidelines by the International Diabetes Federation Task Force28] is a known predictor of atherosclerosis and cardiovascular mortality risks.29 MS is reported in 30% of obese teenagers30 and as high as 95% in SO bariatric adolescents,31 with the implication that obese adolescents will incur similar high cardiac mortality and morbidities as obese adults. Because MS is a hallmark for NASH and is highly associated with liver-related mortality,32 NASH is considered to be a hepatic manifestation of the MS.

Pathology Experimental and clinical works on NAFLD pathogenesis have been thoroughly reviewed elsewhere.33,34 However, our understanding is still incomplete, in part because epidemiological studies relied on a heterogeneous patient population with varying disease courses and non-invasive diagnostic methods without liver biopsy-authenticated NAFLD histology. In addition, there are difficulties in differentiating primary etiologies from epiphenomena or secondary effects of the disease and, as previously mentioned, varying definitions of NAFLD were used among clinical series. We will focus on the adipocytes, the hepatocytes, and the intestinal epithelial cells as key participants in (1) the fat–liver axis and (2) the gut–liver axis during NAFLD pathogenesis. The fat–liver axis: The liver as a metabolic sentinel of adipocyte dysfunction Adipose tissues (adipocytes and stromal cells) release hormones and adipokines to regulate glucose and lipid metabolism. During obesity, the fat-laden visceral adipocytes adapt to the increased fat mass with hypertrophy and acquire a new inflammatory molecular profile. In addition, macrophage infiltration of the abnormal fat tissues exacerbates adipocyte dysfunction and the inflammatory stress response. The underlying inducers of this pathological response are free fatty acids (FFAs) and their toxic metabolic products.35 FFAs activate stress kinases, such as NF-κB by recruitment of Toll-like (TLR-4) receptors, c-Jun, JAK/STAT, protein kinase C, and mTOR pathways, to inhibit adipocyte insulin signaling. Insulin sensitivity is further modulated by inflammatory cytokines, such as TNFa, which cooperate with FFA to alter the

phosphorylation state of insulin receptor substrates.36–38 Insulinresistant adipocytes release excess FFA to distant tissues including muscles, pancreatic endocrine cells, and, in particular, the liver. Ectopic lipid deposition elicits the same stress-signaling pathways causing pancreatic endocrine cells dysfunction, peripheral IR, and hyperinsulinemia. In the liver, increased hepatic FFA flux39,40 and peripheral hyperinsulinemia activates lipogenic transcription factors, such as hepatic sterol regulatory element-binding protein (SREBP-1)41,42 and peroxisomal proliferators-activated receptor PPAR-α, leading to abnormal gluconeogenesis, de novo lipid synthesis, and increased VLDL/apoB metabolism and export. The net effects are systemic hyperglycemia with worsening of hyperinsulinemia (thus increased risks for T2DM), intrahepatic fat accumulation (thus steatosis), and peripheral dyslipidemia. The normal adaptive pathway for lipid disposal is lipid oxidation. Overwhelming lipid burden induces hepatocyte mitochondrial dysfunction, recruits the free oxygen radical-generating microsomal or peroxisomal pathways of lipid oxidation and endoplasmic reticulum (ER) stress,43 and exacerbates the stress kinase and hepatic Kupffer macrophages inflammatory response. With diminished antioxidant response, hepatocytes become more vulnerable to cell death. Phagocytosis of hepatic apoptotic bodies by hepatic stellate cells recruits pro-fibrogenic pathways.44 In summary, hepatocyte and adipocyte cross-talk during obesity plays a central role in the development of steatosis and inflammation. Inflammation excerbates IR, providing the setting for hepatic vulnerability to additional multifactorial insults and progression to hepatocellular damage. Altered hepatic and systemic profile of inflammatory cytokines45; metabolic stressors IR and HTN46; and cytochrome P450 CYP2E1 oxidase47 overexpression have all been found in obese patients and obese NASH patients. However, not all patients with the metabolic syndrome develop hepatic steatosis, and all do not have similar course of progression to steatohepatitis or cirrhosis. A new paradigm of NAFLD pathogenesis disputes the notion of IR as a major hepatic stressor. Because the clinical course of NAFL (steatosis) is rarely progressive, it was proposed that there is no disease continuum from NAFL and NASH but that they are separate entities with distinct histological and pathophysiological features. This implies that alternative approaches to the future study and treatment of NAFLD should be considered.48 Gut–liver cross-talk Intestinal permeability and inflammation as drivers of chronic liver disease are the subject of many excellent reviews.49,50 Briefly, the gut is a large lymphoid organ interfacing outside pathogens and the host. The gut bacterial microflora actively supports intestinal metabolic, digestive, hormonal, and trophic activities. It also modulates the innate host immune response to pathogens. This flora consists of pathogenic, and non-pathogenic bacteria and their by-products such as EtOH and LPS, which in turn can be modified by dietary intake. The leaky gut concept postulates that altered gut–pathogen homeostasis promotes bacterial overgrowth and increased luminal bacterial lipopolysaccharide (LPS). Intestinal TLR recognition of bacterial-specific pathogen-associated molecular patterns stimulates inflammation, impairs intestinal permeability, and facilitates bacterial translocation. Since 70% of the liver vascular inflow is through the portal vein, the liver is the first filter for these pathogens and responds with activation of the innate immune defense by resident macrophages (Kupffer and stellate cells) and NK cells. Experimental models of NAFLD demonstrate that specific intestinal microbiota is obesogenic51 and modulates the disease course.52 Mice with deficiency in the bacterial sensors nod-like receptors (NLRP3) have altered bacterial flora (dysbiosis), with increased hepatic inflammation and more aggressive liver disease course, while mice with TLR mutation develop IR, obesity,

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and systemic inflammation.53 Consistent with these experimental findings, obese patients have dysbiosis, NAFLD/NASH patients have intestinal bacterial overgrowth, and SO patients have distinct BMIand diet-independent NASH microbiome.54,55 Similarly, obese NASH children have accentuated EtOH-producing Escherichia coli intestinal microflora56 and systemic endotoxemia.57 These data provide the basis for current clinical studies into the use of pre-, pro-, and syn-biotics to modify intestinal microbiota as therapeutic options for pediatric NAFLD.58,59 Interestingly, dietary fructose has been shown to promote intestinal bacterial fermentation, LPS-activation of TLR-4, altered intestinal permeability, endotoxemia, systemic inflammation, and IR.60 In the liver, fructose is an easy substrate for glycolysis and gluconeogenesis, thus furthering IR and abnormal lipid metabolism. In humans, fructose has been linked to dyslipidemia, visceral obesity, enhanced susceptibility to MS,61,62 and hepatic fat accumulation in adults63 and children.64 Intestinal incretins and bile acids have recently been linked to glucose metabolism and fatty liver.65,66 Incretins [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] are nutrient-sensing gut hormones with diverse effects on cardiovascular function, satiety, delay of gastric emptying, insulin production, and inhibition of glucagon release. GLP-1 synthetic analogs are currently used for the treatment of T2DM.67 In the liver, GLP-1 modulates hepatic insulin signaling, improves fatty acid oxidation to enhance lipid metabolism by activation of lipolytic transcription factors, and attenuates endoplasmic reticulum stress, providing the basis for the current investigational use of GLP agonists in NAFLD treatment.68,69 Bile acids are major ligands for G-protein-coupled receptor TGF5, which can activate GLP-1. Bile acids also bind to families of lipid-sensing nuclear hormone receptors, such as farnesoid X receptor (FXR), whose signaling pathways are involved in cholesterol, lipoprotein, and glucose metabolism, thus linking bile acids directly or indirectly with hepatic glucose and lipid homeostasis and paving the way to the investigational use of FXR agonists in the treatment of NAFLD.70 It is worth mentioning that a third axis, the neurointestinal cross-talk, is another area for intense investigation linking gut microbiota and vagal afferent pathways with feeding behavior and CNS development.71 To summarize, intrahepatic IR and inflammation can be modulated by the intestinal milieu through diet to modify the gut biotome or the neurohormonal response. Contributing factors Beyond visceral fat, pancreas, gut, and the liver cross-talk, many biological variables have the potential to further modulate NAFLD clinical course. They include the following factors: 1. Gender: the prevalence of NAFLD is twice higher in men.72 The physiological bases include gender differences in fat distribution, more atherogenic lipid profile from enhanced hepatic lipase activity in men, the protective role of estrogens,73–77 or puberty-related hormonal environment potentially affecting teenagers' metabolic response to obesity.78,79 2. Age: the severity of adult NAFLD increases with aging. Older patients have increased prevalence of MS and increased risks for cardiovascular disease.80,81 3. Ethnicity: hispanic patients have been reported to be at a higher risk for MS and NAFLD,82 although this risk may be attributable to a higher incidence of T2DM.83 4. Genetic factors: mutation or polymorphism of metabolic genes such as apolipoprotein C3, phospholipase PNPLA3, endocannabinoids receptor CB2, or the hereditary hemochromatosis HFE gene, which have been linked to progressive NAFLD.84–86

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5. Familial inheritability87 with strong penetrance for the presence of fatty liver. 6. Cytochrome P450 oxidative enzyme CYP2E1 as risk factor for oxidative stress.47,88 7. Abnormal hepatocellular iron metabolism with excess intrahepatic free iron and elevated Hepcidin, a proinflammatory adipokine involved in iron homeostasis.89,90 8. Gestational obesogenic diet as sensitizers to NAFL, which progresses to NASH-like course following postnatal obesogenic diet in experimental models.91 9. Hedgehog signaling (Hh): regulates cell fate determination and activation of progenitor stem cells during morphogenesis. The severity of NASH directly correlates with aberrant Hh signaling in hepatocytes as potential pathogenic or modulator of NAFLD.92

NAFLD Epidemiology The incidence of NAFLD varies greatly as a function of the diagnostic methods and of the population being studied. In the general population, NAFLD's overall prevalence is between 6% and 51%, including 7-11% of patient with abnormal liver function enzymes and up to 74% of liver-biopsy obese patients with metabolic risk factors.14 In the bariatric adult patients, the reported prevalence of NAFLD is between 24% and 98%93 and cirrhosis is 5%,94,95 depending on the histological definition and the methods of sampling96–98 (open biopsies, open-paired biopsies, or percutaneous). The incidence of NAFLD based on abnormal LFT or liver sonograms in the general pediatric population is 7–12% and 80% in obese children. Using the Brunt's and AASLD criteria, paired left and right liver biopsies with 4 8 portal tracts/sample, we found that 63% of the 24 severely obese bariatric adolescent patients had definite NASH and an additional 25% had “borderline” NASH. In contrast, only 25% of adult SO bariatric cohorts with comparable BMI and metabolic profiles have definitive NASH and 25% have “borderline” NASH.99 Hepatic fibrosis is also more prevalent in adolescent SO patients (83% vs 29%), suggesting that SO adolescents may have a more aggressive course of NAFLD. These data stress the need for systematic and rigorous intraoperative liver biopsies for proper NAFLD diagnosis and continued follow-up of NAFLD in SO adolescents into adulthood. This incidence of NASH differs from a separate publication reporting a 20% incidence in SO teens with similar metabolic risk factors.100 NASH diagnosis was based on a NAFLD activity score of 45, a criteria that does not necessarily correlate with pathologic NASH,5 underscoring the need to standardize histological criteria in published materials. There are additional particularities in NAFLD in children.23,101 Pediatric histopathology is distinct, with isolated portal tract abnormalities detected in up to 44% of the patients with pediatric-specific periportal (zone 1) steatosis, inflammation, and fibrosis compared with adult NAFLD pattern, which consists of perivenous (zone 3), lobular, and perisinusoidal histopathologies.99 The portal tract pathology may be peculiar to pediatric NAFLD or merely reflect the natural progression of NAFLD from periportal zone 1 to perisinusoidal zone 3 injuries as these patients mature into adulthood. Interestingly, in our study, both non-obese and SO adolescents have higher baseline serum sCD14 level than the SO bariatric adults, suggesting underlying endotoxemia in the adolescents. Since zone 1 is the first intrahepatic anatomical site in contact with portal blood flow, NAFLD portal injury may reflect an intrinsic anatomical response to intestinal toxins or endotoxemia. For SO teens, predilection for a fructose-rich diet102 and age- or puberty-specific hormonal environment78,79,103 may differentially

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enhance their susceptibility to intestinal bacterial overgrowth to sensitize them to NAFLD. Interestingly, adult bariatric patients were recently reported to have 4 75% incidence of NASH pathology with a high frequency of portal inflammation,104–106 bringing into question the uniqueness of portal tract disease in pediatric patients and emphasizing the need to include SO patients in the broad characterization of the NAFLD spectrum using standardized histological criteria. Diagnosis Patients with NAFLD are often asymptomatic, presenting with vague abdominal pain, hepatomegaly, or mild elevation of aminotransferase ALT levels. However, normal liver function enzymes do not rule out advanced NAFLD and are poor biomarkers for NAFLD.82 Abdominal ultrasound is the most common radiologic test to diagnose steatosis based on increased liver echogenicity. It has good sensitivity for pure steatosis or mild NASH but is operator dependent, lacks standardized interpretations, and is not useful for severe NASH. CT scan and T1-weighted abdominal magnetic resonance imaging (MRI) are expensive alternatives. Overall, as screening tests, they lack good diagnostic sensitivity for NASH, particularly for SO patients.107 While liver biopsy is considered to be the gold standard for NAFLD diagnosis, it has potential issues with sampling inaccuracies or inadequacies, or errors of detection because of the uneven clinical course of NAFLD from changes in life-style or diet.108 Because of the invasiveness, costs, morbidity, and impracticality of performing liver biopsy in at-risk patients, numerous clinical prediction scores using multimodality tests have been proposed. They include NAFLD fibrosis scores (age, BMI, platelet count, albumin, AST/ALT ratio, and dyslipidemia),7 pediatric NAFLD fibrosis index, enhanced liver fibrosis test, fibroscan, transient elastography,109 and circulating CK18 biomarkers for hepatocellular apoptosis23 to name a few. These tests have yet to be validated for widespread use in NASH diagnosis in both adult and pediatric patients. Intraoperative systematic liver biopsy in patients with high-risk for NAFLD is justifiable because of the technical ease and added safety of liver biopsy performed under direct vision, bearing in mind that a liver's grossly normal appearance cannot be relied upon to exclude NAFLD.110,111 Treatment The current consensus is that drug therapy is not recommended for steatosis and that NAFLD treatment should be first directed at weight loss and lifestyle interventions. These interventions improve steatosis when measured by LFT, sonogram, or MRI.1 Lifestyle modification alone may be just as effective as weight loss in lowering NAS or Brunt's NAFLD score.112 Current recommendations call for a 5% loss of excess weight for steatosis and a 10% loss of excess weight for NASH,113 but the effectiveness of weight loss for NASH or fibrosis is inconclusive, given the dearth of studies with biopsy-supported data, while the effect on improving hepatic fibrosis is uncertain.114–116 Interventions for NASH are presently targeting IR and inflammation through insulin sensitizers, such as metformin and Pioglitazone; antioxidants, such as ω-3 fatty acids or vitamin E; or cytoprotective agents, such as Ursodeoxycholic acids.117–119 Because of the heterogeneous patient population and concurrent multimodality treatment in many studies, the real direct effects are not convincing, but early results suggest some improvement of NASH histology with Pioglitazone and vitamin E but the benefits of pharmacotherapy have to be counterbalanced against serious adverse effects such as bladder cancer for Pioglitazone or hemorrhagic stroke for vitamin E.120–122 For pediatric patients, weight loss and lifestyle changes are the cornerstone of NAFLD treatment based on the effects on improved

liver enzymes and sonograms.122 The NASH Clinical Research Network's Treatment of NAFLD in children (TONIC) is a randomized control trial (RCT) with metformin and vitamin E. The study yielded promising results for vitamin E and no benefit for Metformin.119 More recently, an RCT of the use of probiotics or ω-3 fatty acids also reported encouraging early results with improvement of serum liver enzymes but without validating liver histology.59,124 Therefore, the efficacy of drug treatment for NASH remains unproven123,125 and is best offered in the setting of controlled clinical trials. Bariatric surgery Until novel effective treatment becomes available, non-invasive weight loss interventions for SO do not provide significant and durable results and have a high relapse rate,126,127 leaving SO patients with few treatment options other than bariatric surgery. There are 3 major forms of bariatric surgery, the restrictive procedures promoting satiety and delayed gastric emptying (adjustable gastric banding and sleeve gastrectomy), the malabsorptive procedures (biliopancreatic diversion), and the combination procedure [Roux-en-Y gastric bypass (RYGB)]. Bariatric surgery is an accepted weight loss treatment for SO patients meeting the NIH criteria (BMI 440 kg/m2 or BMI 4 35 kg/m2 with comorbidities) and has yielded broad metabolic benefits.128 Bariatric surgery-mediated weight loss improves glycemic control129,130 and MS,131 cures T2DM (in particular for malabsorptive procedures), and increases overall life expectancy.132,133 Metaanalyses of limited series and short-term follow-up of bariatric surgery in SO adolescents demonstrated effective weight loss,134 with preliminary improvement or resolution of metabolic parameters and quality of life. Because of the link between MS and NAFLD, improvement of NAFLD in SO patients would be an expected natural outcome of bariatric surgery's beneficial effects on MS. The mechanisms by which bariatric surgery reduces hepatic injury is loss of fat mass with secondary benefits on systemic inflammation and IR, increases in the profile of good adipokines, and modification of the intestinal microbiotome to the “good” gut flora.135,136 Malabsorptive procedures may have additional gut hormones and nutrient-sensing effects with reduced ghrelin, enhanced GLP-1 secretion, early ileal exposure to nutrients with reduced expression of peptide YY and oxyntomodulin obesogens,137 and altered bile acid metabolism. Significant improvement in steatosis at longitudinal follow-up at 1-year postadult bariatric surgery and sustained benefits at 5 years of bariatric surgery have been demonstrated in a prospective study.138 Metaanalyses showed improvement or resolution of steatosis in over 90% of patients after bariatric surgery.139 While the benefits for steatosis are well established, bariatric surgery as a sole indication for NASH is not universally accepted in spite of the large body of clinical and metabolic data for bariatric surgery showing histological improvement as secondary effects of the weight loss procedure (summarized in Table). Mathurin's138 prospective study showed reduced hepatocyte ballooning at 1- and 5-year longitudinal follow-up and Mummadi's meta-analysis reported improvement of NASH histology in 82% and in the degree of hepatic fibrosis in 66% of the patients.139 The literature consists of many retrospective observational studies and no randomized controlled studies, with variable inclusion criteria, small sample size, lack of clear identification of confounding factors such as IR, MS, and incomplete longitudinal follow up biopsy, providing the basis for the Cochrane meta-analysis140 conclusion that the impact on NASH is unconvincing. Based on the published data, the American College of Gastroenterology, the American Gastroenterological Association and the American Association for the Study of Liver Diseases AASLD stated that while bariatric surgery is not

Table Clinical series105,106,138,146–161 of NAFLD outcome in bariatric SO adult patients are tabulated, showing type of studies (retrospective or prospective); percentage of patients with follow-up biopsy; interval time of liver biopsy; methodology of histologic assessment; and improvement (Imp), resolution (Res), or no change (No) of each of the histologic criteria (steatosis, inflammation, fibrosis, ballooning injury, and cirrhosis). Note the short duration of follow-up, limited number of patients with repeat biopsies, variability in prevalence of NASH, and diverse choice of histologic methods between studies, the rare cases of cirrhosis progression or de novo fibrosis, which are mostly mild changes from previous histology. Improvement in histology is reported in terms of percentage change from initial biopsies and is denoted as Imp (%). References

Study type

F/u biopsy

F/u biopsy

No. of patients

No. of patients

No. of months

?

106

2

16 72 163 35

16 72 93 19

557

61

Histology method

NASH initial (%)

NASH Steatosis change (%) change (%)

Inflammation change (%)

Fibrosis change (%)

Fibrosis worse (%)

Ballooning change (%)

Brunt

Imp

10 7 4.3 15 7 9 12 21.4

Brunt Brunt Authors Dixon

Imp Imp (35) Imp (47) Imp

Imp (80) Imp (57)

Imp (86) Imp (25)

0 0

Imp

Imp (52)

10

16

17

Brunt

Imp (35)

Imp (76)

112

16

24 7 8

Matteoni

Res

Res

Imp (24)

0

Imp (70)

? ? 284

18 39 114

24 18 19 7 8

NAS NAS Authors

67 60

Imp (88) Imp (97) Imp

Imp

Imp (75) Imp (50)

0

Imp (50) Res

644

78

4 12

Braziliian

58

15 59

15 17%

12 41 7 25

Authors Brunt

51

?

18 7 10

Brunt

528

69

27 7 15

36 60 376

36 60 279

26 7 10 30 7 16 12

Brunt NAS

Prospective 689 Retrospective 697

184 78

41 7 25 6 36

Authors Authors

2 100

Imp (89)

29

98

67 70 27

Res

Imp (50)

Fibrosis new (%)

Imp

Imp (53)

Imp (16)

Imp (84) Imp (23) Imp (48)

1 Imp (85)

0 Imp 52)

Imp (45)

Imp

Imp (16)

Imp (16)

Imp (50)

Worse

Imp (40) Imp (16) Imp (54)

Imp (55) Imp (36) No

Imp (70) Imp (35) Worse (35)

Imp (61)

Imp (27) Imp

Cirrhosis F/u (%)

5

Imp 4

Imp

Imp (44)

0 9 “mild”

0 0 1

2% EtOH

A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57

Roux-en-Y gastric bypass Retrospective Silverman et al.159,a Clark et al.106 Prospective Mattar et al.155 Prospective Mottin et al.157 Retrospective Barker Prospective et al.146,a Csendes Prospective et al.147 de Almeida Prospective et al.148 Furuya et al.150 Prospective Retrospective Liu et al.154 Weiner Retrospective 161 et al. Moretto Retrospective et al.156,a Vertical-banded gastroplasty Ranlov et al.158 Prospective Prospective Jaskiewicz et al.152 Prospective Stratopoulos et al.160 Luyckx Retrospective et al.162,a Adjustable gastric banding Dixon et al.105 Prospective Dixon et al.149 Prospective Mathurin Prospective et al.138

Initial biopsy

Imp (69) Imp (31) Imp

Malabsorptivesilv Kral et al.151,a Keshishian et al.153 a

Imp

Imp (58)

23% F0–F1

Imp 3%

Series reporting histologic disease progression.

53

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contraindicated in otherwise eligible obese patients with NAFLD, it is not an "established option for NASH treatment".1 This point of view is reinforced by reports of de novo or progression of NASH or of hepatic fibrosis following bariatric surgery,131 progression to cirrhosis following jejunoileal bypass141,142 or with rapid weight loss,143,144 irrespective of the weight loss procedures. On further analyses, of series describing NASH disease progression, the pathology is not well characterized; the incidence of worsening histology is low, and commonly associated with mild progression in the initial histological grade (Table). Possible etiologies for treatment failure such as the status of metabolic stressors, weight loss outcome that could impact NASH course were not defined; systematic follow up data for the longitudinal changes in the histology was not done, leaving in doubt the true association of bariatric surgery with progression of liver disease. Cirrhosis is considered by many to be a contraindication for weight loss procedure in SO patients because of the associated perioperative mortality,145 the potential risk of disease progression, and the unproven benefits of bariatric surgery on cirrhosis. For bariatric SO teens, weight loss and metabolic benefits have been documented, but NAFLD outcome is non-existent, suggesting the need for educational efforts and advocacy for this health problem in this patient population.

Conclusions To summarize, NAFLD consists of 1) simple fatty liver infiltration (steatosis) or 2) inflammatory NASH (non-alcoholic steatohepatitis), which is highly associated with the metabolic syndrome. NAFLD is becoming the most common cause of chronic liver diseases, with NASH as a predictor for hepatic fibrosis. In the absence of well-validated non-invasive diagnostic criteria and biopsy-confirmed studies, and insufficient long-term and largescale follow-up, the natural history and prognosis of pediatric NAFLD remain undefined, and current analyses and management recommendations for pediatric NAFLD are still evolving. Despite the potential peculiarities of pediatric histopathology, pediatric NAFLD shares with adult NAFLD many of the metabolic risk factors for cardiovascular morbidities and early mortality; as well as disease progression for liver-related morbidities such as cirrhosis and hepatocellular carcinoma. For the SO adult and SO pediatric patients, substantial gaps remain in our knowledge of NAFLD disease characteristics and evolution. Because of the paucity of systematic intraoperative liver biopsy, NAFLD remain under diagnosed in the majority of SO bariatric adolescent patients. A significant number of SO bariatric adolescent patients with liver biopsy data have NASH and hepatic fibrosis. Since hepatic fibrosis is the best predictor for liver-related mortality and complications, NAFLD needs to be recognized as a major pediatric public health threat. Bariatric surgery has well-defined indications for weight loss with clear metabolic benefits in severely obese patients. It improves steatosis and NASH in most of the patients, but not universally. Progression of fibrosis following bariatric surgery has been reported but deserves further studies. Outcome data of NAFLD in SO bariatric adolescents and children is non-existent. Well-designed multidisciplinary large-scale collaborative studies with comprehensive research and clinical database are needed to characterize NAFLD in SO patients, NAFLD natural history and NAFLD liver-related comorbidities following bariatric surgery. Future publications on NAFLD in SO bariatric patients can benefit from clear baseline and longitudinal demographic, anthropomorphic and metabolic characteristics; careful risk stratification; surgical procedure-specific analyses; and systematic liver biopsies with quality biopsy materials and well-defined histological

methods and interpretation. Pediatric surgeons have an important role in assisting with the proper diagnosis, treatment and in furthering the understanding of pediatric NAFLD disease characteristics, evolution and pathogenic mechanisms by diligence in performing systematic intraoperative liver biopsies in high-risk patients undergoing a surgical procedure and by participation in multi- institutional studies. References 1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142: 1592–1609. 2. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474. 3. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321. 4. Alkhouri N, De Vito R, Alisi A, et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J Hepatol. 2012;57:1312–1318. 5. Brunt EM, Kleiner DE, Behling C, et al. Misuse of scoring systems. Hepatology. 2011;54:369–370 [author reply 370–1]. 6. Argo CK, Northup PG, Al-Osaimi AM, et al. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51: 371–379. 7. Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;25:883–889. 8. Angulo P. Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts. Hepatology. 2011;53:1792–1794. 9. Mencin AA, Lavine JE. Nonalcoholic fatty liver disease in children. Curr Opin Clin Nutr Metab Care. 2011;14:151–157. 10. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253. 11. Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–974. 12. Pais R, Charlotte F, Fedchuk L, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013;59:550–556. 13. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873. 14. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–285. 15. Teli MR, James OF, Burt AD, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719. 16. Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138. 17. Yilmaz Y. Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions? Aliment Pharmacol Ther. 2012;36:815–823. 18. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51: 1820–1832. 19. Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–1978. 20. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140. 21. Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis. 2010;28:162–168. 22. Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38: 420–427. 23. Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113– 1120. 24. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58:1538–1544. 25. Reddy SK, Marsh JW, Varley PR, et al. Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: a casecontrol study. Hepatology. 2012;56:2221–2230. 26. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51: 595–602.

A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57

27. Eckel RH, Alberti KG, Grundy SM, et al. The metabolic syndrome. Lancet. 2010;375:181–183. 28. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645. 29. Treeprasertsuk S, Lopez-Jimenez F, Lindor KD. Nonalcoholic fatty liver disease and the coronary artery disease. Dig Dis Sci. 2011;56:35–45. 30. Allcock DM, Gardner MJ, Sowers JR. Relation between childhood obesity and adult cardiovascular risk. Int J Pediatr Endocrinol. 2009;2009:108187. 31. Holterman AX, Browne A, Tussing L, et al. A prospective trial for laparoscopic adjustable gastric banding in morbidly obese adolescents: an interim report of weight loss, metabolic and quality of life outcomes. J Pediatr Surg. 2010;45: 74–78 [discussion 78–9]. 32. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59:1410–1415. 33. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–725.e6. 34. Fujii H, Kawada N. Inflammation and fibrogenesis in steatohepatitis. J Gastroenterol. 2012;47:215–225. 35. Ibrahim SH, Kohli R, Gores GJ. Mechanisms of lipotoxicity in NAFLD and clinical implications. J Pediatr Gastroenterol Nutr. 2011;53:131–140. 36. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45–65. 37. Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab. 2004;30:13–19. 38. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253–259. 39. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351. 40. Fabbrini E, deHaseth D, Deivanayagam S, et al. Alterations in fatty acid kinetics in obese adolescents with increased intrahepatic triglyceride content. Obesity (Silver Spring). 2009;17:25–29. 41. Horton JD, Shimomura I, Ikemoto S, et al. Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. J Biol Chem. 2003;278:36652–36660. 42. Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 1998;12:3182– 3194. 43. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–461. 44. Farrell GC, van Rooyen D, Gan L, et al. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver. 2012;6: 149–171. 45. Bertola A, Bonnafous S, Anty R, et al. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS One. 2010;5:e13577. 46. Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100. 47. Weltman MD, Farrell GC, Hall P, et al. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. 1998;27: 128–133. 48. Yilmaz Y. NAFLD in the absence of metabolic syndrome: different epidemiology, pathogenetic mechanisms, risk factors for disease progression? Semin Liver Dis. 2012;32:14–21. 49. Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: their influences on obesity and obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2013;56: 461–468. 50. Compare D, Coccoli P, Rocco A, et al. Gut–liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2012;22:471–476. 51. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027– 1031. 52. Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–185. 53. Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010;328: 228–231. 54. Ley RE, Turnbaugh PJ, Klein S, et al. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–1023. 55. Sabate JM, Jouet P, Harnois F, et al. High prevalence of small intestinal bacterial overgrowth in patients with morbid obesity: a contributor to severe hepatic steatosis. Obes Surg. 2008;18:371–377. 56. Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–609.

55

57. Alisi A, Manco M, Devito R, et al. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2010;50:645–649. 58. Aller R, De Luis DA, Izaola O, et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15:1090–1095. 59. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2011;52:740–743. 60. Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology. 2013;57:2525–2531. 61. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334. 62. Teff KL, Grudziak J, Townsend RR, et al. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J Clin Endocrinol Metab. 2009;94:1562–1569. 63. Maersk M, Belza A, Stodkilde-Jorgensen H, et al. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr. 2012;95:283–289. 64. Jin R, Le NA, Liu S, et al. Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. J Clin Endocrinol Metab. 2012;97:E1088–E1098. 65. Zarrinpar A, Loomba R. Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;36:909– 921. 66. Lee J, Hong SW, Rhee EJ, et al. GLP-1 receptor agonist and non-alcoholic fatty liver disease. Diabetes Metab J. 2012;36:262–267. 67. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705. 68. Tushuizen ME, Bunck MC, Pouwels PJ, et al. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006;26:1015–1017. 69. Kenny PR, Brady DE, Torres DM, et al. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol. 2010;105:2707–2709. 70. Fuchs M. Non-alcoholic fatty liver disease: the bile acid-activated farnesoid X receptor as an emerging treatment target. J Lipids. 2012;2012:934396. 71. Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009;136:2003–2014. 72. Amarapurkar D, Kamani P, Patel N, et al. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol. 2007;6:161–163. 73. Carr MC, Ayyobi AF, Murdoch SJ, et al. Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women. Arterioscler Thromb Vasc Biol. 2002;22: 667–673. 74. Tikkanen MJ, Nikkila EA. Regulation of hepatic lipase and serum lipoproteins by sex steroids. Am Heart J. 1987;113:562–567. 75. Williams CM. Cardiovascular risk factors in women. Proc Nutr Soc. 1997;56: 383–391. 76. Gutierrez-Grobe Y, Ponciano-Rodriguez G, Ramos MH, et al. Prevalence of non alcoholic fatty liver disease in premenopausal, postmenopausal and polycystic ovary syndrome women. The role of estrogens. Ann Hepatol. 2010;9:402–409. 77. Poustchi H, George J, Esmaili S, et al. Gender differences in healthy ranges for serum alanine aminotransferase levels in adolescence. PLoS One. 2011;6: e21178. 78. Ayonrinde OT, Olynyk JK, Beilin LJ, et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology. 2011;53:800–809. 79. Cook JS, Hoffman RP, Stene MA, et al. Effects of maturational stage on insulin sensitivity during puberty. J Clin Endocrinol Metab. 1993;77:725–730. 80. Chiang CH, Huang CC, Chan WL, et al. The severity of non-alcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population. Clin Biochem. 2010;43:1399–1404. 81. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc. 2002;287:356–359. 82. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395. 83. Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis. Hepatology. 2011;54:837–845. 84. Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. Gastroenterol Hepatol. 2012;35:32–41. 85. Anstee QM, Daly AK, Day CP. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin Liver Dis. 2011;31:128–146. 86. Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol. 1999;31:421–429.

56

A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57

87. Schwimmer JB, Celedon MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1585–1592. 88. Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. 1996;111:1645–1653. 89. Tussing-Humphreys LM, Nemeth E, Fantuzzi G, et al. Elevated systemic hepcidin and iron depletion in obese premenopausal females. Obesity (Silver Spring). 2010;18:1449–1456. 90. Tussing-Humphreys LM, Nemeth E, Fantuzzi G, et al. Decreased serum hepcidin and improved functional iron status 6 months after restrictive bariatric surgery. Obesity (Silver Spring). 2010;18:2010–2016. 91. Mouralidarane A, Soeda J, Visconti-Pugmire C, et al. Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice. Hepatology. 2013;58:128–138. 92. Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711–1721. 93. Gholam PM, Flancbaum L, Machan JT, et al. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol. 2007;102:399–408. 94. Boza C, Riquelme A, Ibanez L, et al. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg. 2005;15: 1148–1153. 95. Beymer C, Kowdley KV, Larson A, et al. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. Arch Surg. 2003;138:1240–1244. 96. Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006;45:600–606. 97. Merriman RB, Ferrell LD, Patti MG, et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology. 2006;44:874–880. 98. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898– 1906. 99. Holterman AX, Guzman G, Fantuzzi G, et al. Nonalcoholic fatty liver disease in severely obese adolescent and adult patients. Obesity (Silver Spring). 2013;21: 591–597. 100. Xanthakos S, Miles L, Bucuvalas J, et al. Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents. Clin Gastroenterol Hepatol. 2006;4:226–232. 101. Giorgio V, Prono F, Graziano F, et al. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr. 2013;13:40. 102. Collino M. High dietary fructose intake: Sweet or bitter life? World J Diabetes. 2011;2:77–81. 103. Roemmich JN, Clark PA, Lusk M, et al. Pubertal alterations in growth and body composition. VI. Pubertal insulin resistance: relation to adiposity, body fat distribution and hormone release. Int J Obes Relat Metab Disord. 2002;26: 701–709. 104. Caballero T, Gila A, Sanchez-Salgado G, et al. Histological and immunohistochemical assessment of liver biopsies in morbidly obese patients. Histol Histopathol. 2012;27:459–466. 105. Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654. 106. Clark JM, Alkhuraishi AR, Solga SF, et al. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res. 2005;13:1180–1186. 107. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–750. 108. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906. 109. Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of nonalcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–649. 110. Dolce CJ, Russo M, Keller JE, et al. Does liver appearance predict histopathologic findings: prospective analysis of routine liver biopsies during bariatric surgery. Surg Obes Relat Dis. 2009;5:323–328. 111. Teixeira AR, Bellodi-Privato M, Carvalheira JB, et al. The incapacity of the surgeon to identify NASH in bariatric surgery makes biopsy mandatory. Obes Surg. 2009;19:1678–1684. 112. Eckard C, Cole R, Lockwood J, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol. 2013;6:249–259. 113. Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci. 2013;1281:106–122. 114. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–1413. 115. Harrison SA, Fecht W, Brunt EM, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009; 49:80–86. 116. Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–974. 117. Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–479.

118. Musso G, Gambino R, Cassader M, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52: 79–104. 119. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. J Am Med Assoc. 2011;305:1659–1668. 120. Mahady SE, Webster AC, Walker S, et al. The role of thiazolidinediones in nonalcoholic steatohepatitis—a systematic review and meta analysis. J Hepatol. 2011;55:1383–1390. 121. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46. 122. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916–922. 123. Vajro P, Lenta S, Pignata C, et al. Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions. Ital J Pediatr. 2012;38: 55. 124. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids—a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31:679–692. 125. Nguyen TA, Sanyal AJ. Pathophysiology guided treatment of nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2012;27(suppl 2)58–64. 126. Yanovski JA, Yanovski SZ. Treatment of pediatric and adolescent obesity. J Am Med Assoc. 2003;289:1851–1853. 127. Yanovski SZ. Pharmacotherapy for obesity—promise and uncertainty. N Engl J Med. 2005;353:2187–2189. 128. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. J Am Med Assoc. 2004;292:1724–1737. 129. DeMaria EJ, Pate V, Warthen M, et al. Baseline data from American Society for Metabolic and Bariatric Surgery-designated Bariatric Surgery Centers of Excellence using the bariatric outcomes longitudinal database. Surg Obes Relat Dis. 2010;6:347–355. 130. Rao RS, Kini S. Diabetic and bariatric surgery: a review of the recent trends. Surg Endosc. 2012;26:893–903. 131. Hafeez S, Ahmed MH. Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: a future treatment by choice or by chance? J Obes. 2013;2013:839275. 132. Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus Ann Surg. 1995;222:339–350 [discussion 350–2]. 133. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122: 248–256.e5. 134. Black JA, White B, Viner RM, et al. Bariatric surgery for obese children and adolescents: a systematic review and meta-analysis. Obes Rev. 2013;14: 634–644. 135. Sweeney TE, Morton JM. The human gut microbiome: a review of the effect of obesity and surgically induced weight loss. J Am Med Assoc Surg. 2013;148: 563–569. 136. Graessler J, Qin Y, Zhong H, et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters. Pharmacogenomics J. 2013;13:514–522. 137. Peterli R, Steinert RE, Woelnerhanssen B, et al. Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial. Obes Surg. 2012;22:740–748. 138. Mathurin P, Hollebecque A, Arnalsteen L, et al. Prospective study of the longterm effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137:532–540. 139. Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6:1396–1402. 140. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010 [CD007340]. 141. Peters RL, Gay T, Reynolds TB. Post-jejunoileal-bypass hepatic disease. Its similarity to alcoholic hepatic disease. Am J Clin Pathol. 1975;63:318–331. 142. Piepkorn MW, Mottet NK, Smuckler EA. Fatty metamorphosis of the liver associated with jejunoileal bypass. Report of five cases. Arch Pathol Lab Med. 1977;101:411–415. 143. D'Albuquerque LA, Gonzalez AM, Wahle RC, et al. Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery. Liver Transpl. 2008;14:881–885. 144. Andersen T, Gluud C, Franzmann MB, et al. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12:224–229. 145. Mosko JD, Nguyen GC. Increased perioperative mortality following bariatric surgery among patients with cirrhosis. Clin Gastroenterol Hepatol. 2011;9: 897–901. 146. Barker KB, Palekar NA, Bowers SP, et al. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. 2006;101:368–373. 147. Csendes A, Smok G, Burgos AM. Histological findings in the liver before and after gastric bypass. Obes Surg. 2006;16:607–611. 148. de Almeida SR, Rocha PR, Sanches MD, et al. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg. 2006;16:270–278.

A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57

149. Dixon JB, Bhathal PS, O'Brien PE. Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic improvement. Obes Surg. 2006;16:1278–1286. 150. Furuya CK Jr, de Oliveira CP, de Mello ES, et al. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J Gastroenterol Hepatol. 2007;22:510–514. 151. Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135:48–58. 152. Jaskiewicz K, Raczynska S, Rzepko R, et al. Nonalcoholic fatty liver disease treated by gastroplasty. Dig Dis Sci. 2006;51:21–26. 153. Keshishian A, Zahriya K, Willes EB. Duodenal switch has no detrimental effects on hepatic function and improves hepatic steatohepatitis after 6 months. Obes Surg. 2005;15:1418–1423. 154. Liu X, Lazenby AJ, Clements RH, et al. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg. 2007;17:486–492. 155. Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg. 2005;242:610–617 [discussion 618–20].

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156. Moretto M, Kupski C, da Silva VD, et al. Effect of bariatric surgery on liver fibrosis. Obes Surg. 2012;22:1044–1049. 157. Mottin CC, Moretto M, Padoin AV, et al. Histological behavior of hepatic steatosis in morbidly obese patients after weight loss induced by bariatric surgery. Obes Surg. 2005;15:788–793. 158. Ranlov I, Hardt F. Regression of liver steatosis following gastroplasty or gastric bypass for morbid obesity. Digestion. 1990;47:208–214. 159. Silverman EM, Sapala JA, Appelman HD. Regression of hepatic steatosis in morbidly obese persons after gastric bypass. Am J Clin Pathol. 1995;104:23–31. 160. Stratopoulos C, Papakonstantinou A, Terzis I, et al. Changes in liver histology accompanying massive weight loss after gastroplasty for morbid obesity. Obes Surg. 2005;15:1154–1160. 161. Weiner RA. Surgical treatment of non-alcoholic steatohepatitis and nonalcoholic fatty liver disease. Dig Dis. 2010;28:274–279. 162. Luyckx FH, Lefebvre PJ, Scheen AJ. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab. 2000;26:98–106.