Review

Nonalcoholic Fatty Liver Disease in Children

Melania Manco, MD, PhD, GianFranco Bottazzo, MD, Rita DeVito, MD, Matilde Marcellini, MD,
Geltrude Mingrone, MD, PhD, FACN, and Valerio Nobili, MD
Scientific Directorate (M.M., GF.B), Dept. of Pathology (R.D.V.) and Hepato-Gastroenterology and Nutrition (V.N., M.M.),
“Bambino Gesu” Children’s Hospital and Research Institute, Dept. of Internal Medicine (G.M.), Catholic University,
Rome, ITALY
Key words: diet, insulin resistance (IR), Metabolic Syndrome (MetS), Non-Alcoholic Fatty Liver Disease (NAFLD),
Non-Alcoholic Steatohepatitis (NASH), pediatric obesity

In view of the epidemic obesity in childhood, facing the disease and its associated morbidities early at this
age becomes crucial for public health researchers and care givers. The present review focuses on pediatric Non
Alcoholic Fatty Liver Disease (NAFLD) among co-morbidities, being the disease yet under diagnosed and under
treated despite a prevalence growing exponentially.
Evidences suggest that the environmental background for the development of NAFLD may be established in
early life, and that the duration of the disease affects probably the likelihood of progression to more severe
disease (necro-inflammation or Non Alcoholic SteatoHepatitis, also termed, NASH; fibrosis and cirrhosis).
NAFLD associates with abdominal obesity, insulin resistance and features of metabolic syndrome. In
genetically prone individuals, malnutrition (i.e., excessive consumption of saturated fats and refined sugars)
leads to the derangement of the adipose tissue architecture and homeostasis, the peripheral and hepatic resistance
to insulin-stimulated glucose uptake, thus favoring a condition of chronic low-grade inflammation. Excessive
nutrients cannot be stored in the adipose tissue and overflow elsewhere, mainly to the muscle tissue and liver.
Fat deposition in both sites enhances insulin resistance and further deposition of fats in a vicious manner.
What is of special interest comparing NAFLD in children and adults is that the histological appearance of
the disease differs significantly, likely representing a yet physiological response to environmental stressors in
children and a long-term adaptation in adults.
In this article, we review the current concepts about paediatric NAFLD, its pathogenesis, diagnosis and
treatment, with particular regard to lifestyle and foods habits.

Key teaching points:

• Pandemic NAFLD parallels increasing prevalence of obesity and components of the metabolic syndrome in children.
• Histology of NAFLD differs in children and adults.
• Obese children with NAFLD show a still naı̈ve response to environmental stressors respect with adults.
• A program targeting gradual weight reduction and physical exercise represents the gold standard for the treatment of NAFLD.
• In the treatment of NAFLD, dietary micro and macronutrient contents should reflect all the acquisitions in the treatment of diseases
clustering in the definition of the metabolic syndrome.

CURRENT SCENARIO IN PEDIATRIC reported from North America, Europe, Australia and Asia [1].
NAFLD. PREVALENCE OF THE It is almost certainly the most common cause of liver disease at
DISEASE this age, with cases described in children as old as 3 years [2].
The increase in its prevalence parallels the epidemic obesity. A
Non Alcoholic Fatty Liver Disease (NAFLD) may be recent survey on adolescent participants in the NHANES
deemed as a worldwide problem in childhood, with case series 1999 –2004 observes that elevated ALT level, a surrogate

Address correspondence to: Melania Manco, MD Ph.D, Scientific Directorate, Bambino Gesù Children’s Hospital, S. Onofrio 4 Square, 00165 Rome, ITALY. E-mail:
melaniamanco@tiscali.it

Journal of the American College of Nutrition, Vol. 27, No. 6, 667–676 (2008)
Published by the American College of Nutrition

667
Pandemic NAFLD in Children
marker of NAFLD in absence of other causes of liver disease,
is present in 8.0% of US adolescents aged 12–19 years [3]. In
a case series of autopsies performed on children 2–19 years of
age at time of death, the prevalence of histological proven
NAFLD is 9.6% [4]. Prevalence of the disease increases when
samples of subjects are selected for obesity. NAFLD is reported
to affect 20% of obese children and adolescents from US [5],
44% from Italy [6] and 74% from China [7]. The disease
associates significantly with type 2 diabetes mellitus [8] and all
features of the metabolic syndrome (MetS) [2].
NAFLD encompasses a spectrum of disease from asymp-
tomatic steatosis, with or without elevated aminotransferases,
to cirrhosis with complications of liver failure and hepatocel-
lular carcinoma [9]. The histological appearance ranges from
simple steatosis to hepatocellular damage coupled with inflam-
mation (i.e., Non Alcoholic SteatoHepatitis, NASH) and/or
fibrosis [10]. Diagnosis of NAFLD requires serial measure-
ments of aminotransferases and ultrasound evaluation of liver
brightness, whilst diagnosis of NASH and fibrosis necessitates
liver biopsy. Therefore, prevalence of NAFLD can be exactly
estimated in obese children, who are referred to secondary care
centers for the treatment of obesity. On the contrary, no accu-
rate information can be provided on the prevalence of NASH.
On the largest two samples of biopsy proven NAFLD described
in the literature [2,11], NASH is diagnosed in 84% of NAFLD
children from the Rome survey [2] and in 68% from the San
Diego sample [11].
PATHOGENESIS: BEYOND THE
“TWO HIT HYPOTHESIS”
After the disease was firstly described in 1980, two decades
later a first hypothesis was formulated on its pathogenesis [12]
and revised shortly [13]. In brief, excessive dietary fats over-
flow to the liver, and fat deposition is the first hit in the model
(simple steatosis or NAFLD). Second insults, yet unknown,
determine the progression from NAFLD to NASH. To date,
several researchers still bet on the pathogenetic role of a num-
ber of mediators as candidate hits. A complex of several agents,
and not a single one, may interact driving NAFLD to NASH.
The interaction between genes and environment begins during
the intrauterine and the early years of life to promote NASH.
To support this hypothesis is the evidence that the disease is
diagnosed in children as old as three years [2], and children
born small weight for gestational age (SGA) have greater
chance to develop NASH [14]. The concept of a genetic-
environment conspiracy as a major basis for the progression of
metabolic diseases (thrifty genotype) applies also to NASH,
which associates almost constantly with obesity, insulin resis-
tance (IR) and all the features clustering in the metabolic
syndrome [2]. Apart from predisposing to the development of
components of the MetS in the adult life, intrauterine factors
seem to be important for liver development and function yet
668
during the gestational life. According to the hypothesis of a
fetal programming, undernutrition in mid and late gestation
results in maintaining the brain at the expense of the trunk
growth, including visceral organs such as the liver [15]. This
causes permanent alterations in the liver function [16]. Con-
trasting our and other’s thesis, the recent survey from the
NHANES 1999 –2004 founds no association of birth weight or
maternal smoking during pregnancy with elevated ALT level
[3].
Children start to eat dense calorie food (“junk food” rich in
both high saturated or hydrogenated fats and high glycaemic
index carbohydrates; sweaty beverages and carbonate drinks),
whilst their physical activity is inadequate to burn excessive
calories. Fats accumulate largely in adipose tissue, and, inap-
propriately, in muscle and liver. The sequence of events leading
to the ectopic accumulation of triglicerydes which causes in-
sulin resistance to develop has been referred to as the “overflow
hypothesis” [18]. Insulin resistance represents a physiological
energy sparing mechanism which favours survival during lim-
ited food availability or increased energy needs, promoting
energy accumulation as fat and reducing energy expenditure.
INSULIN RESISTANCE AND
OXIDATIVE DAMAGE
The role of IR in the progression from NAFLD to NASH is
still unclear. Rate of oxidative and non-oxidative glucose dis-
posal seem to be reduced significantly in patients who develop
NASH compared with those who do not [18], being almost half
of the normal value even in NAFLD patients with no impaired
glucose tolerance [19]. This means that a higher demand of
insulin is needed to maintain euglycemia. Consequently, insu-
lin secretion is enhanced to balance the decreased glucose
disposal [2,18]. The pathogenetic mechanisms sustaining the
relation between IR and development of NAFLD/NASH are,
however, far from the intent of this review. They have been
extensively afforded elsewhere [20]. Therefore, in Fig. 1, we
schematise simply main pathways of this relationship. In brief,
IR results from the inability of the adipose tissue to expand and
to accommodate excess fats. This imbalance favours the exces-
sive release of adipocytokines which further enhances IR in a
vicious cycle. To mediate signalling, insulin receptor uses
docking proteins, such as insulin receptors substrates (IRS).
Tyrosine phosphorylation of IRS is a crucial step which can
activate three major pathways: i) PI3K-Akt pathway involved
in glucose, lipid and protein metabolisms; ii) MAPK pathway
which mediates cell growth and differentiation; iii) CAP/Cbl/
Tc10 pathway, which, in muscle, controls the membrane trans-
location of glucose transporter 4 (GLUT4). In liver, the acti-
vation of PI3K-Akt pathway results in abnormally suppressed
lipolysis, increased gluconeogenesis and de novo lipogenesis
[due to the up-regulation of lipogenic transcription factors_i.e.
the sterol regulatory binding protein-1c (SREBP-1c) and the
VOL. 27, NO. 6

Fig 1. Impaired metabolic pathways in NAFLD/NASH. Grey lines
show the pathways related to insulin resistance; dotted black lines
pathways enhanced in NAFLD/NASH; continuous black lines path-
ways not affected by the above mentioned conditions; continuous red
line pathways inhibited in NAFLD/NASH. Abbreviations: Carnitine
PalmitoylTransferase (CPT-I); Carbohydrate Responsive Element
Binding Protein (ChREBP); Free fatty acids (FFAs); Glucose Stimu-
lated Insulin Secretion (GSIS); Glucose Transporter 4 (GLUT4);
Hydrogen peroxide (H2O2); 4-hydroxynonenal (HNE); Hormone
Sensitive Lipase (HSL); Insulin Receptors Substrates (IRS); Malondi-
aldehyde (MDA); Mitogen Activated Protein kinase, (MAPK); Perox-
isome Proliferators Activated Receptor gamma (PPAR␥); Phosphoino-
sitide 3-kinase, (PI3K); Reactive Oxygen Species (ROS); Respiratory
Chain (RC); Sterol Regulatory Binding Protein-1c (SREBP-1c); Trans-
forming Growth Factor beta (TGF␤); Triglycerides (TG).
carbohydrate response element binding protein (CREBP)] [21–
22]. In fact, while in healthy subjects, the contribution of the de
novo lipogenesis at fast is less than 5% and increases signifi-
cantly after a meal, in patients with NAFLD, lipogenesis is
significantly greater in fasting condition (up to 26% of the
normal rate) and fails to increase in response to a meal [23]. De
novo lipogenesis provides a hepatic holding pool of neo syn-
thesised FAs. A decreased hepatic rate of lipid export, due to
reduced apo-lipoprotein B synthesis and/or excretion and con-
sequently, defective incorporation of triglycerides into the li-
poproteins, may further exacerbate fat storage in liver [23]. The
second pool of fatty acids which contributes significantly to the
systemic lipid overload in NAFLD patients is constituted by
circulating free fatty acids. Plasma FAs are part of a fast
turnover pool and are preferentially incorporated into circulat-
ing lipoproteins. In NAFLD as well as in any similar condition
of peripheral insulin resistance, the flux of FAs from the
adipose tissue is not suppressed by insulin and plasma FAs are
persistently high [23]. Consequently, hypertriglyceridemia, low
HDL concentrations, and small, dense LDL particles are com-
mon features in these patients.
Compensatory pathways to fat accretion in liver and muscle
include activation of mitochondrial FA beta-oxidation due to a
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
Pandemic NAFLD in Children
desensitization of carnitine palmitoyltransferase (CPT-I),
which acts as gate-controller to the entry of long chain FAs into
the mitochondria. Most of the electrons provided to the respi-
ratory chain migrate along the respiratory chain to the cyto-
chrome c oxidase. The imbalance between a high input and a
restricted flow of electrons may cause over-reduction of com-
plexes I and III of the respiratory chain. These overlay reduced
complexes may react with oxygen to form reactive oxygen
species (ROS). Reduction of oxygen at complexes I and III
generates superoxide anion radicals, which are dismutated into
hydrogen peroxide (H2O2) by the superoxide dismutase
(MnSOD). ROS oxidize unsaturated FAs to trigger lipid per-
oxidation to form products such as 4-hydroxynonenal (HNE)
and malondialdehyde (MDA). ROS, reactive nitrogen species
and reactive aldehydic lipid peroxidation products can directly
damage mitochondrial DNA and respiratory chain polypep-
tides. Furthermore, ROS overproduction increases the expres-
sion of several cytokines [TNF-alpha; transforming growth
factor beta, (TGF beta); Fas ligand Fas ; interleukin 8, (IL-8)]
which are able promoting activation of caspases and increase
mitochondrial permeability, neuthrophil infiltration, collagen
synthesis in stellate cells [24]. Antioxidants agents (mainly
glutathione) are rapidly consumed becoming insufficient to
counteract increasing concentrations of ROS, which can pro-
mote necro-inflammation. ROS cause directly cell apoptosis
through the activation of NF-kB (for a review on the relation
between oxidative stress and NASH see [25]).
Several signals from the adipose tissue [i.e., leptin, TNF-
alpha . . .] contribute to enhance hepatic inflammation. In fact,
the maladaptive organization of the adipose tissue architecture
in response to excess nutrients results in generation of inflam-
matory signals inside the adipose tissue particularly in areas in
which cell growth and differentiation are not sufficiently sus-
tained by tight regulation of neo-angiogenesis and stroma gen-
eration. The net result is an inflamed and hypoxic adipose
tissue, which can directly contribute to the progression from
NAFLD to NASH with increased release of TNF-alpha [26]
and leptin [27], and reduced adiponectin [28].
CLINICAL FEATURES AND
DIAGNOSIS
In biopsy-proven series of NAFLD/NASH children, over
90% of subjects are overweight or frankly obese with a prev-
alent abdominal distribution of fat [29]. In fact, very recently,
we and others [3,29] have highlighted the association between
central distribution of adiposity and progression from NAFLD
to NASH, which with insulin resistance are common hallmarks
of NAFLD.
NAFLD children are insulin resistant, as estimated by the
homeostatic model assessment of insulin resistance (HOMA-
IR) with an index of HOMA-IR ⱖ3 [30], mostly are dyslipi-
demic with abnormal levels of circulating triglicerydes and/or
669
Pandemic NAFLD in Children

low HDL-cholesterol. Forty percent are hypertensive; 10%

show impaired glucose tolerance and 2% overt type 2 diabetes
mellitus (T2DM) [2] at the time of diagnosis. Beta cell function
adapts to reduced peripheral insulin sensitivity [2] and subjects
with reduced first phase insulin secretion progress toward di-
abetes in the late adolescence or young adulthood (personal
data, unpublished). Diabetes is diagnosed in up to 8% of
patients [11], metabolic syndrome in 65% [2]. Presence of one
or more factors associated with the MetS enhances greatly the
chance to develop NASH.
NAFLD/NASH is insidious, with most children having no
symptoms or signs of liver disease despite a severe derange-
ment of the liver structure may be established. Some patients
complain of fatigue, malaise, vague and aching right upper
quadrant discomfort. Hepatomegaly is frequently observed.
Achanthosis nigricans, which is regarded as cutaneous marker
of IR, has been reported in 30% of NAFLD children, but it is
extremely uncommon in our [2] as well as in different case
series [31]. Aminotransferases may range from normal to fairly
or severely increased values (by six-seven folds the normality).
Their course may fluctuate over the time and 20% of NAFLD
patients show normal levels at the time of the liver biopsy [2].
Apart from increased levels of liver enzymes, other laboratory
parameters related to liver function are commonly in the nor-
mal range. Signs and symptoms of chronic liver disease (i.e. Fig 2. Diagnostic flow-chart in suspected NAFLD. Dashed grey lines
ascites or variceal haemorrhage) are very uncommon. represent not routinely assays. Abbreviations: Amino Acides (AA);
In presence of increased aminotransferases, ultrasound eval- Antinuclear Antibodies (ANA); Anti-Smooth Muscle Antibody
uation is required to suspect NAFLD. Liver biopsy provides (ASMA); Bioelectric Impedance Analyzer (BIA); Cytomegalovirus
accurate information on the organ damage, allowing discrimi- (CMV); Dual-energy X-ray Absorptiometry (DXA); Epstein Barr Vi-
nating NASH from simple steatosis, to stage the grade of rus (EBV); Euglycemic Hyperinsulinemic Clamp (EHC); Hepatitis
fibrosis and to eliminate competing diagnoses. Staging the Viruses (HAV; HBV; HCV; HEV; HGV); Homeostatic Model Assess-
ment (HOMA); Insulin Resistance (IR); Insulin Sensitivity Index (ISI);
degree of fibrosis is of particular interest since fibrosis may be
Liver Kidney Microsomal antibodies (LKM); Long Chain Free Fatty
associated with progressive liver injury. Not counting the cost,
Acids (LC-FFAs); Quantitative Insulin-Sensitivity Check Index
liver biopsy is not without risk, including haemorrhaging and
(QUICKI); Polimerase Chain Reaction; (PCR); Total Parenteral nutri-
even death. Additional concern may be raised when patients are tion ( TPN).
children and adolescents, thus liver biopsy seems more difficult
to be proposed in paediatric settings. We recommend perform-
ing the biopsy to confirm the diagnosis before starting any appropriate tests. Sensitivity to insulin is evaluated by using
treatment. On the contrary, some Authors prefer to delay this simple derivative methods based on values of glucose and
procedure, starting first a nutritional program and following the insulin in response to a standard glucose challenge [insulin
time course of liver enzymes in the long-term. We describe in sensitivity index (ISI-composite) [33], oral glucose insulin sen-
Fig. 2 the diagnostic flow-chart adopted in our unit. Presence of sitivity (OGIS) [34]], or estimated by more time consuming
metabolic co-factor, i.e. obesity, overweight, or increased vis- although accurate methods [Euglycemic hyperinsulinemic
ceral fat, hyperinsulinemia, insulin resistance, dyslipidemia and clamp (EHC) [35], intravenous glucose tolerance test (IVGTT)
hypertension, augments all the chance to have complicated [36]]. Apart from giving information on the amount of insulin
fatty liver disease [2,29]. Observations in children [3] as well as released in response to a standard oral load, the oral glucose test
in adults suggest that normal weight subjects also may be allows evaluating tolerance to glucose [37]. Accurate clinical
insulin resistant presenting an unhealthy phenotype character- evaluation is useful to identify adolescents who may benefit
ised by increased abdominal distribution of fat [32]. These from screening for NAFLD, thus offering an opportunity to
individuals are prone to develop all the features of the MetS, intervene and prevent disease progression at an early age.
including NAFLD/NASH. Valuable in future screening programs will be the validation of
Both a history of increased levels of aminotransferases for non invasive tests aimed to i) the quantitative assessment of
at least 6 months and evidence of fatty liver at the ultrasounds necro-inflammatory damage; and ii) the detection and/or quan-
require known causes of liver disease to be ruled out by titative assessment of fibrosis. In line with such emerging

670 VOL. 27, NO. 6

 Pandemic NAFLD in Children

needs, some Authors have proposed pooled laboratory param-

eters as means of accomplishing these objectives [38,39]. A
simple scoring system (including age, hyperglycemia, body
mass index, platelet count, albumin, and AST/ALT ratio) ac-
curately separates patients with NAFLD with and without
advanced fibrosis [38]. The European Liver Fibrosis group has
developed and validated to score fibrosis an algorithm combin-
ing age, hyaluronic acid, amino-terminal pro-peptide of type III
collagen, and tissue inhibitor of matrix metalloproteinase [39].
However, there are no scientific evidences proving reliability of
these scores in children. Very recently, the accuracy and repro-
ducibility of transient elastography to stage stage grade of
fibrosis has been evaluated in a sample of children and adoles-
cents with biopsy proven NAFLD. This technology was found
very useful discriminating all children presenting any degree of
fibrosis from those without, but it showed some uncertainness
discriminating exactly between grade of fibrosis 1 and 2. The
results of the study supports the use of this technique in
selected sample of children with suspected NAFLD only and
not yet as screening technique in an unselected pediatric pop-
ulation [40].

LIVER HISTOLOGY
Histological features of NASH differ in childhood respect
with adults [41]. Whilst the adult pattern (termed NASH type 1)
is characterised by the presence of steatosis (mainly macro-
vescicular) with ballooning degeneration and/or perisinusoidal
fibrosis in absence of portal features (Fig. 3A), the pediatric
NASH (NASH Type 2) is defined by the presence of steatosis
along with portal inflammation and/or fibrosis in absence of
ballooning degeneration and perisinusoidal fibrosis (Fig. 3B).
In the San Diego series, NASH type 2 is more common (51
patients out of 100); Type 1 is observed in 17 subjects, and an
overlap of type 1 and 2 is found in 32 cases. When the same
criteria proposed by Schwimmer et al. [41] are applied to the
Rome cohort [42], only 2.4% of 84 patients meet the criteria for
NASH type 1, and 29% the criteria for NASH type 2. The
combination of both types is observed in the largest part of
patients (52%) (Fig. 3C). Simple steatosis is found in the 17%
of the sample. Thus, in the Rome series NASH type 1 is rarely
seen as compared with San Diego survey, while the overlap of
type 1 and 2 pattern is the commonest histological report. In the
Rome series, fibrosis is noted in 58% patients; mostly of mild
severity (stage 1 in 51%), with only 5% patients showing septal Fig 3. Panel A: NASH type 1. Steatosis (S) with ballooning (B), no
fibrosis (stage 3). Fibrosis is significantly associated with older fibrosis and/or inflammation in the portal tract (EE 10X). Panel B:
age, increased body mass index [42], metabolic syndrome and NASH type 2. Steatosis (S) with inflammation (I) and fibrosis in the
its components, decreased insulin secretion and sensitivity [2]. portal tract (EE 10X). Panel C: NASH Overlap. Steatosis (S) and
In the San Diego survey, fibrosis is present in 60% of patients ballooning degeneration (B) are associated with inflammation and
fibrosis in the portal tract (EE 10X).
being moderate to severe in half of them. Cirrhosis is observed
in 3% of children. Fibrosis is positively related to the amount
of fat at the biopsy, and to the presence of lipogranulomas and
portal inflammation [41].

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 671

Pandemic NAFLD in Children
Difference in histological prevalence may resemble the dif-
ferent ethnicity of the two samples: all Caucasians in the Rome
series; mostly Hispanics and Asians in the San Diego sample.
As far as the different patterns of histology observed in children
and adults are concerned, it has been speculated that the liver
responds differently in the pediatric age to an insult which is
not yet inveterate as in the adults. In this context, periportal
damage may represent the earlier stage of the injury [43].
What is more significant is that there is still no consensus on
how to evaluate and score histological features of liver involve-
ment. The scoring system for the semi quantitative evaluation of
NASH, proposed by Elizabeth Brunt et al [44] assesses steatosis,
necro-inflammatory activity (grading) and architectural alterations
related to fibrosis (staging). The system has been developed for
NASH, but it does not seem sufficient for the assessment of
NAFLD. Based on the initial system of Elisabeth Brunt, the
Pathology Committee of the NASH Clinical Research Network
has designed and validated a tailored scoring system that encom-
passes the full spectrum of lesion of NAFLD. This system intro-
duces the NAFLD activity score (NAS) including only features of
active injury that are potentially reversible: steatosis, lobular in-
flammation and ballooning [45].
ROLE OF DIET AND
PHARMACOTHERAPY
Diet
To date, therapeutic strategies for NAFLD/NASH have
revolved around i) identification and treatment of associated
metabolic conditions such as obesity, diabetes and dyslipide-
mia; ii) amelioration of insulin resistance by weight loss, ex-
ercise or pharmacotherapy; iii) use of hepato-protective agents
such as antioxidants to protect liver from secondary insults.
A program targeting gradual weight reduction and physical
exercise continues to be the gold standard of treatment for
NAFLD in children as well as in adults, even though little to no
scientific evidence is available on diet and NAFLD. Change in
lifestyle per sè represents the only effective therapeutic option.
Lifestyle advice, including mainly low-fat and low-glycaemic
index diets and regular physical exercise, causes weight loss,
improvement of body composition, and amelioration up to
resolution of metabolic associated morbidities, including im-
pairment of glucose metabolism, dyslipidemia and blood hy-
pertension [42]. Ultrasound liver brightness and liver enzymes
normalize or improve early after the beginning of the treatment
[42]. This occurs in parallel with the amelioration or resolution
of steatosis and necro-inflammation, while no significant
change comes about grade of fibrosis after two years of a
treatment based on a nutritional counsel alone [46]. A recent
review discusses systematically the effect of macronutrient
content (carbohydrate, fat, and protein ratios) and specific food
components, such as soluble fiber, n-3 fatty acids, and fructose,
672
on fatty liver disease in adults with the intent to enable clini-
cians to evaluate the most appropriate diet for NAFLD/NASH
patients and make rational decisions based on this perspec-
tive—in the absence of controlled trials—to help their patients
[47]. Basically, all the speculations made by the Authors apply
to children, too and are currently in use at our Unit.
First of all, sudden or quick weight loss achieved through
dietary modification may accelerate the progression from sim-
ple fatty liver to NASH, therefore gradual weight loss is
strongly recommended. Consumption of carbohydrate should
be moderate and of low-glycemic index (GI) foods preferred. A
higher carbohydrate intake is associated with a greater odd of
inflammation than a higher fat intake [48]. A recent meta-
analysis [49] has highlighted all the beneficial effects of low in
GI dietary components in individuals with impaired insulin
response and dyslipidemia. According to these evidences, it
seems reasonable to conclude that the inclusion of carbohy-
drates that are high in indigestible and fermentable fiber and
low in GI can be helpful in maintaining glucose, insulin, and
FA concentrations in individuals with IR, such as NAFLD
patients.
Consumption of sweetened drinks causes excess intake of as
much as 150 –300 kcal/d [50]. Therefore intakes of refined
sugars and high-fructose or high-glucose foods and beverages
should be reduced in NAFLD children. High intakes of both
sugars can stimulate de novo synthesis of fatty acids [51] and
lead to changes in long-term energy balance regulation at the
level of the central nervous system, inducing mainly a reduced
post meal suppression of the orexigenic hormone ghrelin [52].
Intake of saturates fats must be limited to ⬍10% of total
energy, since they promote endoplasmic reticulum stress as well as
hepatocyte injury [53], insulin resistance [54] and development of
all components of the metabolic syndrome. Consumption of trans
fatty acids must also be limited. Although the specific pathoge-
netic mechanisms of trans FAs are not yet clear, the recommen-
dation to avoid the intake of those fatty acids deriving from
hydrogenated oils seems well founded, since they may increase
inflammatory markers [55], induce endothelial dysfunction [56],
and unfavorably alter the blood lipid profile [57]. Conversely,
some bacterially derived trans FAs typically found in dairy prod-
ucts seem to not have adverse effects on lipoprotein profiles [58].
Intake of monounsaturated fatty acids (MUFAs) has been largely
recommended. MUFAs are a key component of the Mediterranean
diet, representing the olive oil the main source. The beneficial
effects of MUFAs on cardiovascular disease risk and blood lipid
profiles have been extensively addressed [59], as well as a neutral
in vivo effect on insulin resistance and secretion has been postu-
lated [54]. Contrasting, in part, the latter hypothesis, a recent study
[60] evaluating expression of the phosphatase and tensin homo-
logue on chromosome 10 (PTEN) in the liver of rats and humans
having steatosis, found that oleic acid induces specifically down
regulation of PTEN transcription. PTEN is a major regulator of the
insulin receptor substrate, and its down regulation may favor
VOL. 27, NO. 6

hepatic steatosis and insulin resistance. Therefore, according to
this report, olive oil should be consumed with caution.
Consumption of polyunsaturated fatty acids (PUFAs) is
recommendable as well. PUFAs include n-6 and n-3 fatty acids.
The n-3 fatty acid alpha-linolenic acid is the only dietary
precursor for the docosahexaenoic acid (DHA) and eicosapen-
taenoic acid (EPA), which are essential fatty acids in the
architecture of the membrane phospholipids. A lower n-6 to n-3
ratio seems to be important in determining the metabolic shift
toward beneficial inflammatory pathways [54]. To support the
usefulness of PUFAs in preventing and contrasting NAFLD,
studies have shown that deficiency of essential fatty acids
associates with the development of steatosis in animal models
[61– 62] and that n-3 fatty acids exert positive effects on
amelioration of dyslipidemia and insulin resistance [54]. With
regard to the NAFLD, DHA and EPA can reduce fat depots by
inducing catabolism of fatty acids through the activation of
peroxisome-proliferator activated receptor (PPAR)-mediated
pathways [63] and down-regulate de novo lipogenesis through
SREBP pathways [64].
In our clinical experience, we prescribe patients a hypoca-
loric diet of 25–30 cal/kg/d in case of overweight or overt
obesity, and isocaloric (40 – 45 cal/kg/d) for normal body
weight children, thus inducing a negative calorie balance in the
former and to allow a neutral calorie balance in the latter
subjects. The amount of calories prescribed apart from anthro-
pometrics takes into account physical and daily activities. Diet
composition consists of low GI carbohydrate (50%– 60%); fat
(23%–30%); and protein (15%–20%); with a fat composition of
two in third unsaturated and one in third saturated; the ␻6/␻3
ratio is approximately 4:1 as recommended by the Italian
Recommended Dietary Allowances. Diet is tailored on individ-
ual preferences to improve compliance, which may result par-
ticularly poor in children and adolescents. The above diet
regimen is prescribed with a recommendation to engage in a
moderate daily exercise program (45 min/d aerobic physical
exercise). At each visit, subjects or their parents fill out a three
day dietary and physical activity recall to evaluate adherence to
lifestyle recommendations. A multidisciplinary team including
dieticians, hepatologists, endocrinologists, psychologists, and
cardiologists evaluates and closely follows-up patients. The
weight loss program focuses on long-term dietary modification
(low fat meals, decrease of nutrient dense foods and consequent
increases of fruits and vegetables, ingestion of small to mod-
erate size portions of meals throughout the day), increment in
daily physical activity physical activities and reduction of sed-
entary activities), and behaviour change skills (self monitoring,
family based reinforcement systems, identification of high risk
situations, self awareness, stimulus controls, and cognitive be-
haviour strategies). Participants and their parents are instructed
on how to exercise and maintain adherence to the exercise
program by a skilled exercise physiologist as part of this
multidisciplinary program [42,46].
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
Pandemic NAFLD in Children
Pharmacotherapy
The use of medications for the treatment of NAFLD has
provided uncertain results since there are yet few controlled
studies done in children and adults, which can offer convincing
evidences on the efficacy of a pharmacological approach also
in terms of histological outcomes. A strong rationale supports
the use of certain drugs, i.e. metformin, thiazolidindiones
(TZD) and antioxidants in the treatment of the disease. Vitamin
E may be effective for its antioxidant properties, while met-
formin and TZD for the ability to improve peripheral and
hepatic insulin sensitivity. Metformin has been proved able to
reduce hyperinsulinemia, hepatomegaly in humans [65] and
hepatic steatosis in murine obese models [66]. TZD have been
prescribed only in adults and the administration of pioglitazone
for six month, in a controlled study, was associated with a
greater reduction as compared with the placebo in grade of
necro-inflammation (85% vs. 38%, P ⫽ 0.001) but not of
fibrosis [67].
Vitamin E and Metformin are the only drugs that have been
prescribed in childhood presenting with NAFLD/NASH so far.
A large controlled study granted by the NIH on the use of both
drugs in pediatric NAFLD is now underway [68], even though
the results of the few previous studies are contrasting and not
encouraging at all.
Vitamin E was first prescribed to 11 obese NAFLD
children in an open-label 6 month pilot trial with doses
ranging from 400 to 1200 IU daily [69]. Levels of amin-
otransferases normalized independently of any change in
body weight; however, liver brightness did not improve and
patients experienced an increase in concentrations of liver
enzymes after withdrawing vitamin E therapy. Successively,
Vajro et al [70] observed normalisation of liver enzymes
occurring early after two months of therapy; but again no
changes in liver brightness. The Authors recommended pre-
scribing vitamin E only to those patients with NAFLD who
present with normal body weight.
In a cohort of 90 biopsy proven NAFLD/NASH children,
we have recently observed, in a 2 year controlled study, that
antioxidant supplementation (vitamin E 600 UI/die and vitamin
C 500 mg/die) is not better than placebo, outcomes being
histology, levels of liver enzymes and ultrasound brightness
[46,71].
Same results were obtained by our group after 2 year
treatment with metformin (1500 mg/die) in a clinical trial
running in parallel with the trial on antioxidants and with the
same study design [72].
Before our study, there was a pilot study in which met-
formin alone was administered in ten non diabetic NAFLD
children for six month [73]. Use of metformin (1500 mg/d)
was associated with the improvement of liver histology
with the reduction of fat depot at the magnetic resonance
spectroscopy.
673
Pandemic NAFLD in Children
CONCLUSIONS
Despite a number of acquisitions have enhanced our com-
prehension of NASH/NAFLD pathogenesis in the pediatric
age, it is still unknown, why some patients develop necro-
inflammation and/or necrosis, and others do not and how the
disease will evolve in the adulthood. Its alarming worldwide
diffusion requires growing awareness of the disease by general
practitioners and pediatricians; and recognition of the need to
fight overweight and obesity as the only efficient therapeutic
strategy to battle non alcoholic fatty liver disease.
An acceptable management strategy for an obese child with
NAFLD may attempt to a gradual weight loss using a combi-
nation of diet and exercise in a tight therapeutic multidisci-
plinary long term approach. We recommend adopting a highly
individualized approach for the dietary treatment of the baby
patient, based on a thorough assessment of individual meta-
bolic, physiologic, and nutritional status as well as goals and
preferences. Of course, diet prescription is part of a well-
structured treatment program for maintaining and achieving
weight control which is expected to be more successful than a
simple generic counselling and lifestyle recommendations
made by paediatricians or in a general unit of gastroenterology.
A family based behavioural intervention may enhance self-
motivation and success with diet, since one of the most striking
factors in the clinical practice is the lack of compliance of the
young patient to the treatment, either the only diet or the
pharmacotherapy.
Any attempt to treat pharmacologically NAFLD, at least in
children, did not provide any convincing evidence. Therefore,
even though the use of medications such as anti-oxidants or
metformin seems to be safe and acceptable in terms of costs,
there is no rationale to prescribe them unless conclusive results
are provided.
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Received March 19, 2008; revision accepted July 22, 2008.
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