26 - World Journal of Gastroenterology

genesis through the presence of abnormal lipoprotein
metabolism, especially during the post-prandial phase [76,77] .
Apolipoprotein (APO) B is a large protein involved in the
transport of triglycerides and cholesterol from the liver
to peripheral tissues. Diminished synthesis of APO B,
a rate-determining step in the very low density lipoproteins
(VLDL) assembly, would impair the ability of the
hepatocyte to export triglycerides and cholesterol esters.
Impaired VLDL secretion would also result in increased
levels of atherogenic triglyceride- and cholesterol-rich
remnant particles. Recent studies have suggested a genetic
basis for abnormal lipoprotein metabolism in patients
with NAFLD. Two single-nucleotide polymorphisms in
the gene encoding APOC3 may be associated with hypertriglyceridemia
[78-80] . APOC3 variants C-482T and T-455C
lead to increased plasma concentrations of APOC3, which
in turn inhibit lipoprotein lipase and triglyceride clearance,
thus conferring a predisposition to both fasting and
postprandial hypertriglyceridemia due to an increase in
chylomicron-remnant particles [81] .
THERAPEUTIC APPROACH
The only accepted therapy for pediatric NAFLD is lifestyle
modification with diet and physical exercise. The
close association of NAFLD with MetS and obesity in
children provides the rationale for the therapeutic role of
weight reduction in the treatment of fatty liver disease.
Fortunately, this approach may also be beneficial in improving
cardiovascular risk profile.
Weight-loss oriented lifestyle interventions in the overweight
pediatric population have been shown to increase
glucose tolerance and improve the MetS risk factors [82] .
In children with presumed NAFLD, several studies demonstrate
a normalization of serum ALT associated with
weight loss [5,83,84] . However, the relative efficacy of weight
loss and degree of weight loss needed to induce histologic
improvement in pediatric NAFLD is unknown. Studies in
adults with NAFLD suggest that weight loss also leads to
significant improvement in liver histology. In particular,
a weight loss greater than 5% has been associated with
significant improvement in liver histology [85] . There is only
one clinical trial using liver histology as the primary end
point in children and adolescents with NAFLD [83] . The
study demonstrated that 2 years of lifestyle intervention
with a diet tailored on individual caloric requirement and
increased physical activity was associated with a mean
weight loss of approximately 5 kg, resulting in a significant
improvement in liver histology as well as in insulin
resistance, serum levels of aminotransferases, and lipid
levels. No information exists on recommending any type
of diet. A low-carbohydrate diet has been shown to lead
to a reduction in serum ALT and fatty liver content in
adult patients [86] . A randomized controlled study in obese
adolescents has demonstrated that a diet based on a reduced
glycemic load is more effective than a low fat diet in
achieving weight loss [87] , but similar data are not available in
children with NAFLD. Current data on the role of a low
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Pacifico L et al . Pediatric NAFLD and cardiovascular risk
fructose diet in children with NAFLD are inconclusive [71] .
A 6-month pilot study in children with NAFLD showed
that a low fructose diet was associated with a significant
decrease in oxidized LDL-c [88] . However, no effect on
serum ALT concentrations was found. N-3 long-chain
polyunsaturated fatty acids (LCPUFA) including eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA)
have been reported to control some of the metabolic
stigmata of obesity [89] . Dietary N-3 LCPUFA lower blood
triglycerides and have anti-inflammatory as well as insulinsensitizing
effects [89] . A recent randomised clinical trial has
shown that the supplementation of DHA improves liver
steatosis and insulin sensitivity in children with NAFLD [90] .
Their role in prevention of CVD is also emerging [91] . At
this time, however, the available information is insufficient
to derive dietary intake recommendations for EPA and
DHA [92] . Finally, diet duration and amount of weight loss
have not been definitively assessed in children [83,93,94] .
A general consensus exists about the key role of physical
activity and its synergic effect when combined to diet
modifications. Increasing energy expenditure is an additional
way to reducing daily calories. Liver biopsy has
shown improvement of histologic features in children with
NAFLD who were engaged in a moderate daily exercise
program (45 min/d aerobic physical exercise) associated to
dietary changes [83] .
Owing to the likely role of insulin resistance and
oxidative stress in the development and progression of
NAFLD, most studies on pharmacological treatment have
focused on the use of metformin or antioxidants. These
drugs have been found to be effective in pilot studies [3] .
Recently, in a multicenter, randomized, placebo-controlled
clinical trial of treatment with metformin, vitamin E, or
placebo for 96 wk in 173 nondiabetic children with histologically
confirmed NAFLD, the Nonalcoholic Steatohepatitis
Clinical Research Network found that compared with
placebo, neither vitamin E nor metformin was associated
with a sustained reduction in serum ALT [95,96] . Compared
to placebo, vitamin E significantly improved hepatocellular
ballooning and NAFLD activity score and, in the subset
of children with NASH at baseline, significantly increased
resolution of NASH. Metformin had no significant effect
on any secondary histologic outcome [96] . Neither vitamin E
nor metformin had significant effects on fibrosis, lobular
inflammation, or portal inflammation scores. No significant
differences in safety were reported between groups [96] .
However, the likelihood that vitamin E would need to be
taken indefinitely [97] underlines the importance of longterm
prospective studies involving patients with NASH to
assess the effect of vitamin E on liver-related and cardiovascular
mortality [98] .
Given the role of obesity in the pathogenesis of
NAFLD, bariatric surgery has been proposed as a potential
treatment strategy. In obese adult patients, bariatric
surgery has been shown to induce weight loss, ameliorate
cardiovascular risk factors, resolve hepatic steatosis and, in
most studies, inflammation [99-101] . NASH was improved in
the majority of affected patients and was intimately associ-
3087 July 14, 2011|Volume 17|Issue 26|