Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
COMMENTARY
Non-alcoholic fatty liver disease in non-obese
children
Katarzyna Zdanowicz, MD1; Irena Białokoz-Kalinowska, PhD, MD2; Dariusz M Lebensztejn, PhD, MD1
1 Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
2 Medical Institute, Lomza State University of Applied Sciences, Lomza, Poland
Corresponding author: Ms Katarzyna Zdanowicz (kazdanowicz@gmail.com)
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a
broad spectrum of liver diseases, morphologically
characterised by fat accumulation in >5% of
hepatocyte in the absence of other cause of
steatosis.1 Less-common factors of hepatic steatosis
include metabolic disorders (eg, cystic fibrosis,
Wilson’s disease, alpha-1 antitrypsin deficiency,
galactosaemia, hereditary fructose intolerance),
general or systemic disorders (eg, celiac disease,
hepatitis C, obstructive sleep apnoea, type 1
diabetes), starvation, malnutrition, total parenteral
nutrition, and drug toxicity.2
In recent decades, the increase in the prevalence
of NAFLD is related to the global obesity epidemic
and is considered to be a hepatic manifestation of
the metabolic syndrome.2 Exposure to certain factors
such as maternal overnutrition, gestational diabetes
mellitus, Caesarean section, intrauterine growth
retardation, and antibiotic use during pregnancy and
infancy may be associated with an increased risk of
NAFLD in children. In contrast, breastfeeding is a
potential protective factor.3
Recent data have shown that NAFLD can
occur in patients with a normal body mass index
(BMI). Metabolically obese, lean NAFLD patients
are non-obese subjects (BMI <95th percentile of
age, overweight is not an exclusion criterion) with
or without coexisting increased waist circumference
and visceral adipose tissue.2
Epidemiology
The incidence of lean NAFLD in adolescents varies
widely, ranging from 8% in the US4 to 16% in the
Asia-Pacific region.4 5 Large discrepancies in the
occurrence rates may be related to different inclusion
criteria and cut-off points for non-obese NAFLD.6 7
The prevalence of lean NAFLD differs significantly
due to urbanisation and wealth of different regions of
the world, as well as the associated diet and physical
activity levels.8
Visceral adiposity
According to Javed et al,9 BMI may be wrongly
classified in over a quarter of children with excess
adiposity. In a cohort study of 126 subjects between
11 and 17 years with similar total fat values, NAFLD
patients had higher amount of visceral fat tissue.10
Owing to the importance of visceral adiposity, the
least invasive and easily accessible methods are
necessary. One of the proposed techniques is sagittal
abdominal diameter (SAD), which is measured
with a sagittometer as the distance between the
calliper blades at the end of normal expiration.
There is no consensus on the optimal landmark for
SAD measurement. The anteroposterior diameter
is measured in supine position, which allows
for the displacement of subcutaneous adipose
tissue laterally. Yim et al11 considered the ability
of SAD to index abdominal fat more precisely
than waist circumference and BMI, particularly
among young and lean patients. Compared with
other anthropometric measurements such as
waist circumference, waist-to-hip ratio, and BMI,
SAD showed stronger correlations with metabolic
syndrome risk factors.12
Genetic and environmental factors
Genetic factors associated with increased risk
of developing NAFLD in non-obese patients
include nucleotide polymorphisms in patatin-like
phospholipase domain-containing 3 (PNPLA3)
[rs738409], cholesteryl ester transfer protein (CETP)
[rs12447924 and rs12597002], transmembrane 6
superfamily member 2 (TM6SF2), and apolipoprotein 3 (APCO3) [rs2854116 and rs2854117].2 13 The
microsomal triglyceride transfer protein (MTP),
membrane-bound O-acyltransferase domain-containing
protein 7 (MBOAT7), peroxisome
proliferator-activated receptor-γ coactivator
(PPARGC1A), heme oxygenase-1 (HO-1), and
hypoxia inducible factor 3 alpha subunit (HIF3A)
genes represent NAFLD risk factors in the paediatric population, but to date studies have only involved obese children.13
The relationship between dietary fructose
intake and NAFLD has also been described. In a
study of non-obese young patients, it was found that
sweetened beverage consumption was the stand-alone
risk factor of NAFLD development.14 Another
important factor is a high cholesterol diet, even if
the overall energy density is not excessive. Oxysterol
(a metabolite of cholesterol), which is a ligand for
the liver X receptor and mediating sterol regulatory
element-binding protein 1c activation, can initiate
fatty acid synthesis and stimulate lipogenesis (Fig).15
Clinical and metabolic
characteristics
There is a paucity of data on the clinical characteristics
of children with lean NAFLD. Most of studies have
shown that lean subjects with NAFLD are younger,
male with lower BMI and waist circumference
compared with obese NAFLD.2 Comparing
adolescents with lean NAFLD and healthy controls,
hypertriglyceridaemia, higher levels of aspartate
aminotransferase and gamma-glutamyl transferase
were found, but the differences in the levels of total
cholesterol, low-density lipoprotein, and high-density
lipoprotein were not statistically significant.4
In a Korean study comparing obese and non-obese
paediatric patients with NAFLD, triglyceride and
total cholesterol levels were significantly higher in
the lean NAFLD group. However, levels of alanine aminotransferase, aspartate aminotransferase,
gamma-glutamyl transferase, low-density
lipoprotein, high-density lipoprotein, and uric acid
did not differ between groups.16 Non-obese NAFLD
subjects, deprived of other metabolic risk factors,
more frequently had insulin resistance.17 In the US,
insulin resistance was found to be more common in
lean adolescents with NAFLD than in lean healthy
controls, although this difference was not statistically
significant.4
Histological features
Liver biopsy is the gold standard in diagnosing
and grading the severity of NAFLD.1 There have
been limited studies devoted to the evaluation of
histological features in lean children with NAFLD.
In one which evaluated intrahepatic iron in patients
with NAFLD, no histological differences in liver
damage were found among paediatric patients
with NAFLD with normal weight, overweight, or
obesity.18
Screening
Population screening for NAFLD is not recommended
in children but should be considered in high-risk
populations.1 Because NAFLD is often an incidental
finding, especially in patients with normal body
weight, anthropometric measures should be a
routine procedure in examination protocol in search
of abdominal obesity. The diagnostic approach for
patient with NAFLD is as follows. The first stage is the evaluation of alanine aminotransferase activity
(comparable with obese patients). The aetiology of
elevated serum alanine aminotransferase is usually
established through an insightful assessment of
medical history, a series of screening blood tests for
causes of chronic liver disease. Owing to the limited
amount of data on the use of supportive imaging
studies to assess hepatic steatosis in lean children,
no recommendations have been made.2
Treatment
To date, there are no guidelines for treating
non-obese patients with NAFLD. Decreased
consumption of fructose-sweetened food and soft
drinks may be appropriate.2 Increased physical
exercises, especially aerobic exercise, can reduce
hepatic lipid concentration and visceral adipose
tissue.19 At present, pharmacological therapy for
NAFLD is directed at improving the components
of metabolic syndrome. In cases of lean NAFLD,
one of the therapeutic options seems to be
liraglutide, a glucagon-like peptide-1 analogue. In
a randomised placebo-controlled study, liraglutide
led to histological resolution of non-alcoholic
steatohepatitis in adults with lean NAFLD.20 In 2019
the US Food and Drug Administration approved
liraglutide for treatment of paediatric patients aged
≥10 years with type 2 diabetes. Studies of evaluating
glucagon-like peptide-1 analogues in paediatric
patients with NAFLD was not conducted.
Conclusion
No data are currently available on the natural history
and prognosis for lean paediatric NAFLD patients.
Owing to their correct body mass, hepatic steatosis is
often under-recognised. Only lifestyle interventions
are recommended, including a comprehensive
approach to weight management, healthy diet, and
exercise.
Author contributions
All authors contributed to the concept of the study, acquisition
and analysis of the data, drafting of the manuscript, and
critical revision of the manuscript for important intellectual
content. All authors had full access to the data, contributed to
the study, approved the final version for publication, and take
responsibility for its accuracy and integrity.
Conflicts of interest
All authors have disclosed no conflicts of interest.
Funding/support
This commentary received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References
1. Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN clinical practice guideline for the diagnosis and
treatment of nonalcoholic fatty liver disease in children:
recommendations from the Expert Committee on
NAFLD (ECON) and the North American Society of
Pediatric Gastroenterology, Hepatology and Nutrition
(NASPGHAN). J Pediatr Gastroenterol Nutr 2017;64:319-
34. Crossref
2. Wang AY, Dhaliwal J, Mouzaki M. Lean non-alcoholic fatty
liver disease. Clin Nutr 2019;38:975-81. Crossref
3. Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE.
Developmental origins of NAFLD: a womb with a clue. Nat
Rev Gastroenterol Hepatol 2017;14:81-96. Crossref
4. Conjeevaram Selvakumar PK, Kabbany MN, Lopez R,
Rayas MS, Lynch JL, Alkhouri N. Prevalence of suspected
nonalcoholic fatty liver disease in lean adolescents in the
United States. J Pediatr Gastroenterol Nutr 2018;67:75-9. Crossref
5. Fu CC, Chen MC, Li YM, Liu TT, Wang LY. The risk factors
for ultrasound-diagnosed non-alcoholic fatty liver disease
among adolescents. Ann Acad Med Singapore 2009;38:15-7.
6. WHO Expert Consultation. Appropriate body-mass index
for Asian populations and its implications for policy and
intervention strategies. Lancet 2004;363:157-63. Crossref
7. Alberti KG, Zimmet PZ. Definition, diagnosis and
classification of diabetes mellitus and its complications.
Part 1: Diagnosis and classification of diabetes mellitus
provisional report of a WHO consultation. Diabet Med
1998;15:539-53. Crossref
8. Liu CJ. Prevalence and risk factors for non-alcoholic
fatty liver disease in Asian people who are not obese. J
Gastroenterol Hepatol 2012;27:1555-60. Crossref
9. Javed A, Jumean M, Murad MH, et al. Diagnostic
performance of body mass index to identify obesity as
defined by body adiposity in children and adolescents:
a systematic review and meta-analysis. Pediatr Obes
2015;10:234-44. Crossref
10. Ramírez-Vélez R, Izquierdo M, Correa-Bautista JE, et al.
Liver fat content and body fat distribution in youths with
excess adiposity. J Clin Med 2018;7:528. Crossref
11. Yim JY, Kim D, Lim SH, et al. Sagittal abdominal diameter
is a strong anthropometric measure of visceral adipose
tissue in the Asian general population. Diabetes Care
2010;33:2665-70. Crossref
12. Ohrvall M, Berglund L, Vessby B. Sagittal abdominal
diameter compared with other anthropometric
measurements in relation to cardiovascular risk. Int J Obes
Relat Metab Disord 2000;24:497-501. Crossref
13. Goyal NP, Schwimmer JB. The genetics of pediatric
nonalcoholic fatty liver disease. Clin Liver Dis 2018;22:59-71. Crossref
14. Assy N, Nasser G, Kamayse I, et al. Soft drink consumption
linked with fatty liver in the absence of traditional risk
factors. Can J Gastroenterol 2008;22:811-6. Crossref
15. Enjoji M, Yasutake K, Kohjima M, Nakamuta M. Nutrition
and nonalcoholic fatty liver disease: the significance of
cholesterol. Int J Hepatol 2012;2012:925807. Crossref
16. Kim EJ, Kim HJ. Nonalcoholic fatty liver disease in
obese and nonobese pediatric patients. Korean J Pediatr
2019;62:30-5. Crossref
17. Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance
in non-diabetic patients with non-alcoholic fatty liver
disease: sites and mechanisms. Diabetologia 2005;48:634-42. Crossref
18. Manco M, Alisi A, Real JF, et al. Early interplay of intra-hepatic
iron and insulin resistance in children with non-alcoholic
fatty liver disease. J Hepatol 2011;55:647-53. Crossref
19. Johnson NA, Sachinwalla T, Walton DW, et al. Aerobic
exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology
2009;50:1105-12. Crossref
20. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety
and efficacy in patients with non-alcoholic steatohepatitis
(LEAN): a multicentre, double-blind, randomised, placebo-controlled
phase 2 study. Lancet 2016;387:679-90. Crossref