26 - World Journal of Gastroenterology
26 - World Journal of Gastroenterology
26 - World Journal of Gastroenterology
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Pacifico L et al . Pediatric NAFLD and cardiovascular risk<br />
(15.5% vs 7.5%). No significant differences in causes <strong>of</strong><br />
death were found between non-NASH patients and the<br />
corresponding reference population [15] . In a cohort study<br />
involving 173 patients retrospectively identified as having a<br />
diagnosis <strong>of</strong> biopsy-proven NAFLD, Rafiq et al [16] showed<br />
that after a median follow-up <strong>of</strong> 18.5 years, patients with<br />
histologic NASH had significantly higher liver-related mortality<br />
than the non-NASH NAFLD cohort (17.5% vs 2.7%).<br />
The most common causes <strong>of</strong> death were coronary artery<br />
disease, malignancy, and liver-related death. In a very recent<br />
study involving a cohort <strong>of</strong> 118 subjects with NAFLD<br />
who underwent liver biopsy because <strong>of</strong> elevated liver enzymes,<br />
Söderberg et al [17] confirmed that, after a 28-year<br />
follow-up, overall survival was reduced in subjects with<br />
NASH, whereas bland steatosis with or without severe<br />
fibrosis was not associated with any increase in mortality<br />
risk in comparison with the general population. The main<br />
causes <strong>of</strong> death among patients with NAFLD were CVD,<br />
followed by extrahepatic cancers and hepatic diseases. All<br />
these data provide evidence <strong>of</strong> an increased risk for cardiovascular<br />
mortality in patients with NASH. However, most<br />
studies which examined the natural history <strong>of</strong> NAFLD<br />
were retrospective cohort studies with relatively small numbers<br />
<strong>of</strong> patients with histologically proven NAFLD who<br />
were seen at tertiary referral centers - features that limit<br />
the generalizability <strong>of</strong> the findings to a community-based<br />
practice where patients may have a milder disease. Indeed,<br />
among people with NAFLD, those who are referred to<br />
hepatologists may have a more advanced liver disease than<br />
those detected in the community or population based<br />
screening but are not referred. Therefore, the magnitude<br />
<strong>of</strong> mortality risk in NAFLD depends on the setting and<br />
method <strong>of</strong> ascertainment. Future longitudinal studies with<br />
larger and less selected cohorts <strong>of</strong> patients are needed<br />
to identify through reliable, noninvasive means the true<br />
impact <strong>of</strong> the wide spectrum <strong>of</strong> NAFLD in the general<br />
population on the long-term overall and cardiovascular<br />
mortality.<br />
Data on the prognosis and clinical complications <strong>of</strong><br />
NAFLD in children remain scant [3] . Although coronary<br />
artery disease and stroke usually occur in middle and late<br />
age, autopsy studies have shown that the atherosclerotic<br />
process in the vascular wall begins in childhood and is accelerated<br />
in the presence <strong>of</strong> risk factors [18-24] . Given the<br />
large number <strong>of</strong> children affected, it is imperative that<br />
we establish a better understanding <strong>of</strong> the natural history<br />
<strong>of</strong> pediatric NAFLD in terms <strong>of</strong> the progression <strong>of</strong><br />
liver disease as well as its complications (including longterm<br />
cardiovascular risk pr<strong>of</strong>ile). Feldstein et al [34] recently<br />
reported the first longitudinal study describing the longterm<br />
survival <strong>of</strong> children with NAFLD who underwent<br />
a follow-up <strong>of</strong> up to 20 years. That study demonstrated<br />
that NAFLD in children is a disease <strong>of</strong> progressive potential.<br />
Some children presented with cirrhosis, others<br />
progressed to advanced fibrosis or cirrhosis during followup,<br />
and some developed end-stage liver disease with the<br />
consequent need for liver transplantation. Feldstein et al [34]<br />
also showed that NAFLD in children is associated with<br />
WJG|www.wjgnet.com<br />
significantly shorter long-term survival than the expected<br />
survival in the general population <strong>of</strong> the same age and<br />
sex. Children with NAFLD had a 13.8-fold higher risk <strong>of</strong><br />
dying or requiring liver transplantation than the general<br />
population <strong>of</strong> the same age and sex. The recorded deaths<br />
were not liver-related.<br />
Recent epidemiological studies in adult subjects have<br />
also demonstrated that NAFLD is associated with an increased<br />
risk <strong>of</strong> incident CVD that is independent <strong>of</strong> the<br />
risk conferred by traditional risk factors and components<br />
<strong>of</strong> the MetS [35-42] . Yet, several studies (including the pediatric<br />
population) have reported independent associations<br />
between NAFLD and impaired flow-mediated vasodilatation<br />
(FMD) and increased carotid-artery intimal medial<br />
thickness (cIMT) - two reliable markers <strong>of</strong> subclinical atherosclerosis<br />
- after adjusting for cardiovascular risk factors<br />
and MetS [10,12,43-47] .<br />
NAFLD AND MARKERS OF SUBCLINICAL<br />
ATHEROSCLEROSIS IN CHILDREN<br />
The relation between obesity and atherosclerosis development<br />
has been evaluated in many pediatric studies [48] ,<br />
but few studies focused on the relation between NAFLD<br />
and atherosclerosis (Table 1) [32,47,49-56] . In an autopsy study<br />
involving 817 children (aged 2 to 19 years) who died <strong>of</strong><br />
external causes (accident, homicide, suicide) from 1993 to<br />
2003, Schwimmer et al [49] showed that the prevalence <strong>of</strong><br />
atherosclerosis was increased by a factor <strong>of</strong> 2 among those<br />
with NAFLD. Atherosclerosis was assessed as absent, mild<br />
(aorta only), moderate (coronary artery streaks/plaques),<br />
or severe (coronary artery narrowing). Fatty liver was present<br />
in 15% <strong>of</strong> the children. For the entire cohort, mild<br />
atherosclerosis was present in 21% and moderate to severe<br />
atherosclerosis in 2%. Atherosclerosis was significantly<br />
more common in children with fatty liver than those without<br />
the disease (30% vs 19%, P < 0.001). Body mass index<br />
(BMI) was not independently correlated to the presence <strong>of</strong><br />
atherosclerosis, but fatty liver status and BMI did interact<br />
significantly (P < 0.01). Consequently, for obese subjects<br />
the odds <strong>of</strong> having atherosclerosis was more than 6 times<br />
higher in children with fatty liver than those without [49] .<br />
Despite this, there are currently few data regarding the<br />
possible association between liver histopathologic changes<br />
and atherogenic risk in children [32,52,56] . In the Bogalusa<br />
heart study in children, investigators found that the extent<br />
to which the intimal surface was covered with atherosclerotic<br />
lesions was significantly associated with elevation <strong>of</strong><br />
concentrations <strong>of</strong> total cholesterol (TC), low-density lipoprotein<br />
cholesterol (LDL-c), triglycerides (TG), and lower<br />
concentration <strong>of</strong> high-density lipoprotein cholesterol<br />
(HDL-c). Ratios <strong>of</strong> cholesterol ester-rich lipoprotein level<br />
(TC/HDL-c and LDL-c/HDL-c) are well-established<br />
predictors <strong>of</strong> C VD [57] . More recently, the TG/HDL-c<br />
ratio has been shown to be a strong predictor <strong>of</strong> MetS<br />
and CVD [58,59] . In a case-control study, Schwimmer et al [32]<br />
showed that children with a biopsy-proven NAFLD had<br />
a significantly higher fasting glucose, insulin, TC, LDL-c,<br />
3084 July 14, 2011|Volume 17|Issue <strong>26</strong>|