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

a r t i c l e in fo a b s t r a c t

Obesity is a multi-organ system disease with underlying insulin resistance and systemic chronic
Keywords: inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the underlying
Nonalcoholic fatty liver disease metabolic dysfunction. This review provides a highlight of the current understanding of NAFLD
Metabolic dysfunction pathogenesis and disease characteristics, with updates on the challenges of NAFLD management in
Adolescent morbid obesity 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 underman-
aged. 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 non-
alcoholic steatohepatitis (NASH) characterized by steatosis, inflam-
mation, 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
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 classi-
fication 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 histo-
logical score (PNHS) recently incorporated histologic scores of
portal inflammation in its own classification.
Clinical significance

n
Correspondence to: 420 NE Glen Oak, Suite 201, Peoria, Illinois 61603. NAFLD, specifically NASH, is currently the primary cause of liver
E-mail address: aixuan.l.holterman@osfhealthcare.org (A. Holterman). function abnormalities and chronic liver disease in adults7 and in

1055-8586/$ - see front matter Published by Elsevier Inc.

http://dx.doi.org/10.1053/j.sempedsurg.2013.10.016

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50 A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57
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 liver-
related 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 complica-
tions.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/cirrho-
sis.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 decom-
pensated end-stage liver disease requiring liver transplanta-
tion,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 pre-
dictor 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 adoles-
cents 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 under-
standing 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 epipheno-
mena 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 hor-
mones 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 inflam-
matory 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
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phosphorylation state of insulin receptor substrates.36–38 Insulin-
resistant 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 fac-
tors, 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 syn-
thesis, and increased VLDL/apoB metabolism and export. The net
effects are systemic hyperglycemia with worsening of hyperinsu-
linemia (thus increased risks for T2DM), intrahepatic fat accumu-
lation (thus steatosis), and peripheral dyslipidemia. The normal
adaptive pathway for lipid disposal is lipid oxidation. Overwhelm-
ing lipid burden induces hepatocyte mitochondrial dysfunction,
recruits the free oxygen radical-generating microsomal or perox-
isomal pathways of lipid oxidation and endoplasmic reticulum
(ER) stress,43 and exacerbates the stress kinase and hepatic Kupffer
macrophages inflammatory response. With diminished antioxi-
dant 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 excer-
bates IR, providing the setting for hepatic vulnerability to addi-
tional 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 pathophysiolog-
ical 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 molec-
ular patterns stimulates inflammation, impairs intestinal perme-
ability, 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,
 A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57
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 BMI-
and 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 metabo-
lism. In humans, fructose has been linked to dyslipidemia, visceral
obesity, enhanced susceptibility to MS,61,62 and hepatic fat accu-
mulation 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 polypep-
tide (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 recep-
tors, 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 modu-
lated 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 distribu-
tion, 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, endocanna-
binoids receptor CB2, or the hereditary hemochromatosis HFE
gene, which have been linked to progressive NAFLD.84–86
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51
5. Familial inheritability87 with strong penetrance for the pres-
ence of fatty liver.
6. Cytochrome P450 oxidative enzyme CYP2E1 as risk factor for
oxidative stress.47,88
7. Abnormal hepatocellular iron metabolism with excess intra-
hepatic 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 biop-
sies, 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 intra-
operative 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 histopatholo-
gies.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
52 A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57
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 pathol-
ogy 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 amino-
transferase 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 pedia-
tric 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 recom-
mended for steatosis and that NAFLD treatment should be first
directed at weight loss and lifestyle interventions. These inter-
ventions 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 improv-
ing hepatic fibrosis is uncertain.114–116 Interventions for NASH are
presently targeting IR and inflammation through insulin sensi-
tizers, 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
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liver enzymes and sonograms.122 The NASH Clinical Research
Network's Treatment of NAFLD in children (TONIC) is a random-
ized 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 malab-
sorptive procedures (biliopancreatic diversion), and the combina-
tion 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 con-
trol129,130 and MS,131 cures T2DM (in particular for malabsorptive
procedures), and increases overall life expectancy.132,133 Meta-
analyses 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 param-
eters 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 addi-
tional 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 oxyntomo-
dulin obesogens,137 and altered bile acid metabolism. Significant
improvement in steatosis at longitudinal follow-up at 1-year post-
adult bariatric surgery and sustained benefits at 5 years of bariatric
surgery have been demonstrated in a prospective study.138 Meta-
analyses 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 histo-
logical 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 longitu-
dinal follow-up and Mummadi's meta-analysis reported improve-
ment 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
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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 Initial F/u biopsy F/u biopsy Histology NASH NASH Steatosis Inflammation Fibrosis Fibrosis Fibrosis Ballooning Cirrhosis
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

biopsy method initial (%) change (%) change (%) change (%) change (%) worse (%) new (%) change (%) F/u (%)

No. of No. of No. of

patients patients months

Roux-en-Y gastric bypass

Silverman Retrospective ? 106 2 61 Brunt Imp Imp (50) 1

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

et al.159,a
Clark et al.106 Prospective 16 16 10 7 4.3 Brunt Imp Imp (80) Imp (86) 0 Imp (85)
Mattar et al.155 Prospective 72 72 15 7 9 Brunt Imp (35) Imp (57) Imp (25) 0
Mottin et al.157 Retrospective 163 93 12 Authors 2 Imp (47)
Barker Prospective 35 19 21.4 Dixon 100 Imp (89) Imp Imp Imp (52) 10
et al.146,a
Csendes Prospective 557 16 17 Brunt 29 Imp (35) Imp (76)
et al.147
de Almeida Prospective 112 16 24 7 8 Matteoni Res Res Imp (24) 0 Imp (70)
et al.148
Furuya et al.150 Prospective ? 18 24 NAS 67 Imp (88) Imp Imp (75) 0 Imp (50)
Liu et al.154 Retrospective ? 39 18 NAS 60 Res Imp (97) Imp (50) Res
Weiner Retrospective 284 114 19 7 8 Authors Imp Imp 0 Imp
161
et al.
Moretto Retrospective 644 78 4 12 Braziliian 58 Imp (53) Imp 52) 5 4
et al.156,a
Vertical-banded gastroplasty
Ranlov et al.158 Prospective 15 15 12 Authors Imp (45) Imp Imp
Jaskiewicz Prospective 59 17% 41 7 25 Brunt
et al.152
Stratopoulos Prospective 51 ? 18 7 10 Brunt 98 Imp (16) Imp (16) Imp (16) Imp (44) 0
et al.160
Luyckx Retrospective 528 69 27 7 15 Imp (50) Worse 9 “mild”
et al.162,a
Adjustable gastric banding
Dixon et al.105 Prospective 36 36 26 7 10 67 Imp (84) Imp (40) Imp (55) Imp (70) 0 Imp (69)
Dixon et al.149 Prospective 60 60 30 7 16 Brunt 70 Imp (23) Imp (16) Imp (36) Imp (35) 0 2% EtOH Imp (31)
Mathurin Prospective 376 279 12 NAS 27 Imp (48) Imp (54) No Worse (35) 1 Imp
et al.138
Malabsorptivesilv
Kral et al.151,a Prospective 689 184 41 7 25 Authors Imp (61) Imp (27) 23% F0–F1 Imp
Keshishian Retrospective 697 78 6 36 Authors Imp Imp (58) Imp 3%
et al.153

a
Series reporting histologic disease progression.

53
54 A. Holterman et al. / Seminars in Pediatric Surgery 23 (2014) 49–57
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 infiltra-
tion (steatosis) or 2) inflammatory NASH (non-alcoholic steatohe-
patitis), 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 large-
scale 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, anthropomor-
phic and metabolic characteristics; careful risk stratification;
surgical procedure-specific analyses; and systematic liver biopsies
with quality biopsy materials and well-defined histological
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For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
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 charac-
teristics, 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.
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