REVIEW

Risk Factors for Progression of and

Treatment Options for NAFLD in
Children
Phillipp Hartmann, M.D.,* and Bernd Schnabl, M.D.†,‡

Nonalcoholic fatty liver disease (NAFLD) is a common
disease and can affect both adults and children. It is
defined as a long-standing hepatic steatosis that is not
due to genetic or metabolic disorders, infections, side
effects of medication, alcohol consumption, or malnutri-
tion. Pediatric NAFLD occurs in children 18 years or youn-
ger. Alanine aminotransferase (ALT) cutoffs for the
diagnosis of NAFLD have been determined to be 22 mg/
dL for girls and 26 mg/dL for boys in the United States.
NAFLD is linked to obesity and insulin resistance, but also
to dyslipidemia with high triglyceride, high low-density
lipoprotein (LDL), and low high-density lipoprotein (HDL)
cholesterol levels. NAFLD can be subgrouped into several
entities, with the main pathologies being nonalcoholic
fatty liver (NAFL), nonalcoholic steatohepatitis (NASH),
and end-stage cirrhosis, which can be associated with
similar complications in children as seen in adults (see
Table 1 for definitions).1 This review highlights several
risk factors for NAFLD progression to NASH in children,
examines novel treatment options, and investigates the
role of the intestinal microbiome in NAFLD.
DEMOGRAPHIC AND CLINICAL FACTORS
ASSOCIATED WITH NAFLD AND
PROGRESSION TO NASH IN CHILDREN
Several factors determine the risk for NAFLD progres-
sion to NASH in children (Fig. 1).
Demographics. Pediatric NAFLD is more likely to be pre-
sent in boys than in girls and more likely in adolescents
than in toddlers. The risk for NAFLD is directly propor-
tional to the body mass index (BMI), with obese children
being most at risk for NAFLD. The Hispanic population
has a higher risk for NAFLD than Asian or white children.

Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; EtOH, ethanol; LPS, lipopolysaccharide; NAFLD, nonalcoholic
fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing 3.
From the Departments of *Pediatrics and †Medicine, University of California San Diego, La Jolla, CA, and ‡Department of Medicine,
VA San Diego Healthcare System, San Diego, CA.
This study was supported by National Institutes of Health grant R01 AA020703.
Potential conflict of interest: Nothing to report.
Received 31 August 2017; accepted 13 November 2017

View this article online at wileyonlinelibrary.com

C 2018 by the American Association for the Study of Liver Diseases
V

11 | CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD
REVIEW Progression and Treatment of Pediatric NAFLD Hartmann and Schnabl

TABLE 1. SPECTRUM OF NONALCOHOLIC FATTY involved in lipid metabolism, is more common in Hispanic
LIVER DISEASE individuals and has been independently associated with
NAFLD and NASH.3
Type Definition

NAFLD Wide spectrum of conditions, all with long-standing hepatic

steatosis, not due to genetic or metabolic disorders,
infections, side effects of medication, alcohol consumption,
or malnutrition
NAFL At least 5% of hepatic fat by imaging or histology, without
inflammation, with or without fibrosis
NASH Hepatic steatosis and liver inflammation (‘‘-hepatitis’’),
with or without fibrosis
Cirrhosis End-stage liver disease in the setting of NAFLD
Spectrum of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD
encompasses non-alcoholic fatty liver (NAFL) with  5% fat content;
non-alcoholic steatohepatitis (NASH) with fatty liver and liver inflamma-
tion (both entities with or without fibrosis); and NAFLD with cirrhosis
which represents hepatic end-stage disease.
Based on data from Vos et al.1
Black children are least likely to experience NAFLD (Table
2).2 Hispanic children have also been found to be more
at risk for NASH. Interestingly, a single-nucleotide poly-
morphism in the patatin-like phospholipase domain-
containing 3 (PNPLA3) gene (SN rs738409 C>G),
Diet. Fructose consumption has been associated with
NAFLD severity in both cross-sectional and interven-
tional studies. There is evidence that fructose consump-
tion was independently associated with NASH in obese
children with NAFLD; it also showed that fructose
intake was independently linked to hyperuricemia.4 An
intervention with a low-fructose diet in pediatric NAFLD
demonstrated that fructose intake correlated strongly
with plasma ALT, aspartate aminotransferase (AST),
and insulin resistance, independently of weight loss.5
Furthermore, a recent study showed that a 9-day-long
fructose restriction led to significantly decreased liver
fat, visceral fat, and hepatic de novo lipogenesis in
obese children.6
Metabolic Syndrome. Individual features of metabolic
syndrome, in particular central obesity and insulin resis-
tance, were found to be associated with severity of
NAFLD in children.7 In addition, dyslipidemia, hyperurice-
mia, prediabetes, and diabetes were associated with a
higher risk for pediatric NASH.4,8

TABLE 2. PREVALENCE OF NONALCOHOLIC FATTY

LIVER DISEASE (NAFLD) IN CHILDREN
Variable Group Prevalence of NAFLD (%)

Gender Male 11.1

Female 7.9
Age 2-4 years 0.7
5-9 years 3.3
FIG 1 Risk Factors for Progression of Non-Alcoholic Fatty Liver
Disease (NAFLD) to Non-Alcoholic Steatohepatitis (NASH) in Chil- 10-14 years 11.3
dren. Multiple risk factors for progression to NASH have been 15-19 years 17.3
identified, such as diet (e.g., fructose) and metabolic factors, for
example, metabolic syndrome, in particular dyslipidemia, hyper- Ethnicity Black 1.5
uricemia, diabetes mellitus type 2, and possibly an increased BMI White 8.6
z score. Specific ethnicities and genetic setups have been found
Asian 10.2
to be more susceptible to NASH, for example, Hispanic subjects
and subjects with polymorphisms in the PNPLA3 gene. Other risk Hispanic 11.8
factors for the progression to NASH, such as physical inactivity, BMI 5% 0
older pediatric age, or high birth weight, are conceivable or have
been suggested by single studies, but robust scientific evidence is >5% to < 85% 5
still lacking. Abbreviations: NAFLD, nonalcoholic fatty liver dis- 85% to < 95% 16
ease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like
95% 38
phospholipase domain-containing 3.
Based on data from Schwimmer et al.2

12 | CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD
REVIEW Progression and Treatment of Pediatric NAFLD Hartmann and Schnabl

FIG 2 Simplified model of intestinal Stages in the development of nonalcoholic fatty liver disease (NAFLD) and ways probiotics can inter-
vene. Adverse environmental, metabolic and genetic factors such as diet rich in fat or fructose can cause intestinal dysbiosis with reduc-
tion of beneficial bacteria and increase of deleterious bacteria. Dysbiosis results in increased intestinal permeability, or ‘‘leaky gut’’, by
disruption of tight junction proteins such as zonula occludens-1 and occludin. Associated metabolic changes in the bacteria lead to -
amongst others - depletion of choline (which is metabolized to trimethylamine [TMA]), and production of ethanol (EtOH). EtOH and
microbial products, e.g. lipopolysaccharides (LPS), translocate from the intestine into the blood circulation and travel to the liver. In the
liver, choline deficiency promotes steatosis, and EtOH and LPS cause more liver inflammation and finally NAFLD/nonalcoholic steatohepa-
titis (NASH). Probiotics (living non-pathogenic microorganisms such as Lactobacilli and Bifidobacteria that have a favorable impact on the
host) work on several levels. They attenuate intestinal dysbiosis and metabolic changes, and ameliorate the ‘‘leaky gut’’ by preventing
inflammation and apoptosis of the enterocytes, and by inducing tight junction proteins. Probiotics thereby decrease translocation of bac-
terial products and metabolites into the blood stream, which eventually alleviates liver injury. Abbreviations: EtOH, ethanol; LPS, lipopoly-
saccharide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TMA, trimethylamine.

NOVEL TREATMENTS and/or liver inflammation/oxidative stress. A few studies

Currently, pediatric NAFLD is mostly managed by life-
style modifications including a healthy, well-balanced
diet without sugar-sweetened beverages, daily moderate-
to high-intensity exercise, and less than 2 hours of screen
time per day.1
Only a relatively small number of pediatric drug trials
have been conducted for NAFLD/NASH and have thus far
focused on hepatic lipid metabolism, insulin resistance,
have shown that vitamin E (with lifestyle interventions)
results in an improvement of ALT levels in pediatric
patients with NAFLD similar to controls. One study dem-
onstrated that high-dose vitamin E over 2 years resulted
in significantly better NAFLD activity scores and greater
resolution of NASH when compared with controls
despite similar ALT levels.1 A few short-term studies with
probiotics, or living nonpathogenic microorganisms such
as Lactobacilli and Bifidobacteria that have a favorable

13 | CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD
REVIEW Progression and Treatment of Pediatric NAFLD Hartmann and Schnabl
impact on the host,9 showed improvement of pediatric
NAFLD/NASH either with regard to ALT levels or hepatic
steatosis. Fifty-two weeks of cysteamine bitartrate
delayed release (CBDR), a potent antioxidant, led to sig-
nificant reductions in serum aminotransferase levels and
lobular inflammation, but not to significant improvement
of overall histological markers of NAFLD compared with
placebo. Several studies demonstrated that omega-3
fatty acids (docosahexaenoic acid [DHA]/eicosapentaenoic
acid [EPA]) ameliorate liver steatosis on ultrasound and
insulin sensitivity, improve liver and visceral fat, fasting
insulin and/or lipid serum levels relative to placebo; how-
ever only one showed modest improvement of ALT lev-
els. and improve liver and visceral fat, fasting insulin,
and/or.1
In summary, several drugs have been tested in pediat-
ric NAFLD/NASH trials and resulted in some improvement
with regard to systemic ALT levels, hepatic steatosis on
ultrasound, and/or liver histology. However, most have
not led to significantly better outcomes in relation to pla-
cebo/lifestyle intervention only.
ASSOCIATION BETWEEN THE INTESTINAL
MICROBIOME AND NAFLD
Children with NASH harbor significantly higher intestinal
amounts of the gram-negative bacteria Proteobacteria,
Enterobacteriaceae, and ethanol (EtOH)-producing Escheri-
chia than healthy children.10 Intriguingly, children with
NASH have also been shown to have significantly higher
serum levels of EtOH, which can promote gut permeabil-
ity.9,10 In addition, they harbor fewer of the beneficial Bifi-
dobacteria than healthy children.10 This is an example of
intestinal dysbiosis, or a microbial imbalance with its associ-
ated deleterious effects on the colonized host.9 Dysbiosis is
linked to translocation of bacterial products, for example,
lipopolysaccharides (LPS) from gram-negative bacteria, into
the bloodstream. The latter is facilitated by increased intes-
tinal permeability (‘‘leaky gut’’) and is a hallmark event in
the development of NAFLD/NASH, with subsequent
hepatic steatosis and inflammation.11 Antibiotics, prebiotics
(complex carbohydrates nondegradable by humans pro-
moting the growth of beneficial bacteria), and probiotics
are aiming at preventing this translocation9 (for more
details, refer to Fig. 2, as well as Hartmann et al.9 and
Schnabl and Brenner11). Given the likelihood that resistant
pathogenic bacteria could be selected, no antibiotic trials
14 | CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018
for pediatric NAFLD have been conducted. Despite promis-
ing results from studies with rodents (using oligo-fructose
or lactulose), clinical trials for pediatric NAFLD/NASH with
prebiotics have not been carried out yet. A few encourag-
ing interventions with probiotics in children with liver dis-
ease have been completed (see above). However, longer
trials with larger sample sizes are necessary to confirm
these results and possibly demonstrate robust improve-
ment of both liver steatosis and ALT levels in pediatric
NAFLD before routine use can be recommended.
In conclusion, lifestyle intervention including diet and
physical exercise regimens remains the most important
intervention for NAFLD for now. However, our under-
standing of the role of the intestinal microbiome in the
development of NAFLD/NASH is evolving and supports a
potential role of probiotics and possibly prebiotics in
pediatric NAFLD/NASH, also in light of a favorable side
effect profile.
CORRESPONDENCE
Phillipp Hartmann, M.D., Department of Pediatrics, University of Cali-
fornia San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA 92093.
Telephone: 858-822-5311; FAX: 858-822-5370; E-mail: phhart-
mann@ucsd.edu
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