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Noninvasive Evaluations of Non-alcoholic Fatty
Liver Disease in Pediatric Populations
Karen J Campoverde Reyes1,2*, Aysha Aslam1 and Pir Ahmad Shah1
1Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America
2Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
Submission:December 12, 2018;Published: January 17, 2019
*Corresponding author: Karen J Campoverde Reyes, Liver Center, BIDMC, Harvard Medical School, 110 Francis Street, Suite 4A, Boston, MA 02115, USA
How to cite this article: Karen J C R, Aysha A, Pir Ahmad S. Noninvasive Evaluations of Non-alcoholic Fatty Liver Disease in Pediatric Populations. Adv
002 Res Gastroentero Hepatol. 2019; 12(1): 555829. DOI: 10.19080/ARGH.2019.12.555829.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the pediatric population Schwimmer JB et al. , Anderson et al.  & Le et al. . NAFLD in children is associated with central obesity and insulin resistance Alterio & Vos et al. [4,5]. The prevalence of NAFLD in children with obesity is estimated to be 34.2%. That is significantly higher than the 7.6% among children from the general population Anderson et al. . The understanding of the pathogenesis of NAFLD is essential to ensure the finding of a reproducible and accurate noninvasive tool to effectively detect the progress of hepatic steatosis Loomba . This mini review focuses on the currently available noninvasive diagnostic modalities that can potentially be applied in children populations.
The natural history of NAFLD progresses from steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. The term NASH is specifically associated with inflammation and subsequent fibrosis compared to simple steatosis. The stage of liver fibrosis has been identified as the strongest predictor of overall mortality and liver disease complications in adults Angulo et al. . NAFLD-related cirrhosis is currently the second leading cause for liver transplantation in adults Charlton et al. . The risk of hepatocellular carcinoma (HCC) increases with cirrhosis; however, recent report suggests that HCC can also develop in non-cirrhotic NAFLD Welzel et al. . Patients with NAFLD are at higher risk of having other complications such as type 2 diabetes mellitus, cardiovascular diseases, and cancer compared to the general population Lonardo et al. . Similarly, children with NAFLD also were noted to have increased cardiovascular risk and systemic health complications Baskar . The natural history of NAFLD in pediatric populations has not been well established due to the paucity of prospective longitudinal studies. Available
cross-sectional studies suggested that the entire spectrum of NALFD also occur in children. Nobili et al.  However, the prognosis and clinical complications of NAFLD in pediatric populations need to be carefully evaluated by prospective studies.
Simple steatosis, or fatty liver, occurs early in NAFLD and may not be associated with elevated liver enzymes. Moreover, up to 23% of children with NAFLD can have a normal ALT even with the presence of liver fibrosis. Schwimmer, et al. , Mencin , Schwimmer, et al.  & Temple et al. . It is estimated that 25% of pediatric patients with NAFLD will progress to NASH. In a study on pediatric NAFLD patients, 5 had serial liver biopsies over 5 years. Four of them were noted to have progressive advanced fibrosis Feldstein AE et al. .
Liver biopsy is considered the gold standard for diagnosing and evaluating the severity of NAFLD. It is, however, an expensive invasive procedure associated with sampling error and potential serious complications. Its acceptance in the pediatric population is, therefore, limited Kalia et al.  & Le et al. .
Noninvasive modalities to monitor disease progression in pediatric patients with NAFLD are greatly needed. Abdominal ultrasound is readily available but has limited sensitivity. It can only detect moderate to severe fatty infiltration of the liver (≥ 30% steatosis). Furthermore, it is operator-dependent and cannot quantify fat and fibrosis Bouchi, et al. , Jiang ZG, et al.  & Mencin . Despite their limitations, abdominal ultrasound and serum aminotransferases remain the first choice in screening NAFLD in children Temple et al. . Magnetic resonance elastography (MRE) can quantify steatosis and fibrosis with high accuracy and reliability in patients with NAFLD but it has limited availability and is not cost-effective as a screening
modality Temple, et al.  & Dulai et al. . Transient
elastography (Fibro-scan) is another relatively new noninvasive
method for the assessment of liver steatosis and fibrosis. It is fast
with generally accurate and reproducible results. It is, however,
less reliable in pediatric patients with obesity and is not available
in most community hospitals in USA Francavilla .
Pathogenesis of NAFLD is complex and is directly
associated with the metabolism of lipoproteins. The lipolysis
of subcutaneous adipose tissue and intrahepatic and intraabdominal
fat leads to an increase in fatty acids, with an increase
in intrahepatic triglycerides (IHTG) content. That subsequently
leads to elevated production of VLDL and triglycerides. Fatty
acid overload in the hepatocytes results in an impairment of
the insulin signal pathway causing decreased insulin action on
glycogen synthase with subsequent insulin resistance increase in
glucose secretion. Hepatocytes attempt to dispose the excessive
triglyceride accumulation in the liver by increasing the VLDL
secretion. However, the generation of free fatty acids and VLDL is
not balanced, it is actually ineffective and results in inflammation
and accumulation of fat in the liver. With the increasing fat
deposition in the liver, the processing of intrahepatic fats via
various lipoproteins such as low density -LDL, very low density-
VLDL, high density-HDL is also altered, resulting in change in
the serum concentration of these molecules Nobili et al. 
Fabbrini et al. , Jiang ZG et al. , Lavine et al.  & Perla
et al. .
Lipoprotein analysis by Nuclear Magnetic Resonance (NMR)
is an assay that provides lipoprotein information based on the
lipid methyl signals. A given size particle has a constant number
of terminal lipid methyl groups and each lipoprotein particle of
a particular size has its own NMR signature. NMR spectrum is
analyzed to provide particle concentrations for each of the VLDL,
LDL and HDL subclasses. By size VLDL particles, for example,
can be divided as large (>60 nm), medium (42-60 nm), and small
(29-42 nm). Likewise, LDL particles can separate into large
(20.5-23 nm) and small (18-20.5 nm) particles; HDL particles are
classified into 3 categories by size: large (9.4-14 nm), medium
(8.2-9.4nm) and small (7.3-8.2 nm). Some of the advantages of
using NMR detection include negligible sample preparation,
unbiased detection and its inherently quantitative without the
need for control standard.
In adults, it has been shown that the progression of NAFLD
is accompanied by distinctive changes in very low-density
lipoprotein (VLDL) Jiang ZG et al. , Garcia et al.  & Amor
et al. . In a single center study of adult patients with NAFLD,
an increase in VLDL particle size was noted to be association
with both NAFLD activity score (NAS) and NASH. In addition, a
decrease in small VLDL particle concentration was associated
with more advanced liver fibrosis Jiang ZG et al., . Hence, this
NMR profile of lipoprotein particles can potentially be used as
a reliable method to detect progression of NAFLD in the future.
Its availability along with its noninvasive nature could hold a
special interest in the pediatric population. These interesting
and important observations need to be further validated in
both adult and pediatric populations before it can be applied to
clinical practice. It is imperative to find noninvasive and costeffective
tools that can accurately monitor progression of NAFLD
in the clinical settings of pediatric populations [29-31].