Hepatic Steatosis Is Highly Prevalent Across the Paediatric Age Spectrum, Including in Pre-school Age Children

J. Dhaliwal; G. B. Chavhan; E. Lurz; A. Shalabi; N. Yuen; B. Williams; I. Martincevic; A. Amirabadi; P. W. Wales; W. Lee; S. C. Ling; M. Mouzaki

Disclosures

Aliment Pharmacol Ther. 2018;48(5):556-563. 

In This Article

Discussion

In a cohort of previously healthy paediatric trauma patients from Ontario, Canada, 15% 95% CI (12%–18%), were found to have evidence of hepatic steatosis using abdominal CT scans. The proportion of patients with hepatic steatosis was not different across the paediatric age spectrum with 17% of preschoolers having radiological evidence of hepatic steatosis. Abdominal subcutaneous adipose tissue, which is reflective of obesity, was significantly elevated in subjects with hepatic steatosis, particularly younger children, while abdominal visceral adipose tissue was higher in those with hepatic steatosis who were older (≥9.8 years). ALT elevation two times above the upper limit of normal was a poor predictor of hepatic steatosis.

The prevalence of hepatic steatosis measured in this cohort is consistent with paediatric studies from other parts of the world that have used a variety of different approaches to determine the presence of NAFLD.[1] In a meta-analysis of studies that had used serological (ALT elevation), imaging (ultrasound, CT scans, magnetic resonance imaging) or histological evidence of liver injury and/or steatosis, Anderson et al reported the prevalence of NAFLD in the general population to be 7.8% and to surpass 30% in those who are obese. In our cohort, the lack of height measurements precluded us from calculating the BMI but our measured prevalence is consistent with that expected among the Canadian paediatric population in which the reported prevalence of obesity is approximately 13%.[16] There is a paucity of longitudinal studies evaluating the natural history of hepatic steatosis in children and adolescents, and the significance of radiological incidental findings remains unclear.

Non-alcoholic fatty liver disease typically diagnosed between the ages of 10–13 years, which may have to do with screening practices.[18,19] In our cohort there was a significant proportion (17%) of previously healthy preschoolers with evidence of hepatic steatosis. There is a relative paucity of data regarding the prevalence of hepatic steatosis in very young children. The Study of Child and Adolescent Liver Epidemiology (SCALE), retrospectively reviewed autopsies of 742 children (age 2–19 years) and found the prevalence of NAFLD in preschool children to be 0.7% (2–4 years).[20] Beacher et al, recently reported in cohort of obese preschool children (2–5 years), 26% had elevated ALT levels (defined as >30 IU/L).[21] The US Preventive Services Task Force currently advises clinicians to screen for obesity in children and adolescents 6 years and older.[22] However, according to the National Health and Nutrition Examination Survey, 8.1% of infants and toddlers have a high weight for recumbent length.[23] Given the results of our study and the reported rates of obesity in infants and toddlers, we suggest that all children be screened for obesity and that NAFLD be considered a common comorbidity. Further research will help to determine the burden of non-alcoholic fatty liver disease in this young group of children.

It is now widely acknowledged that central adiposity is associated with metabolic dysfunction. Adiposity is broadly divided into subcutaneous adipose tissue, compromising >80% of total body fat and visceral adipose tissue, usually <10% of total body fat in children.[24] Distribution of fat varies in children with both visceral and subcutaneous adiposity typically increasing throughout childhood and adolescence.[24,25] Both pre and post-puberty, females preferentially deposit fat in the gynoid, with subcutaneous adipose tissue increasing more in girls than boys,[26] and this gender difference was evident in our cohort (P < 0.001). In contrast, pubertal and post-pubertal boys tend to deposit visceral adipose tissue in the abdominal region, which was not evident in our cohort.[26,27] There is a paucity of longitudinal studies describing changes in adiposity in children and adolescents, and the studies performed to date have not reliably controlled for total body fat.

In spite of adult literature suggesting that central adiposity and increasing visceral adiposity are risk factors for NAFLD,[28,29] the relationship between increasing adiposity in children and adolescents and increasing visceral adiposity remains unclear. Fox et al reported that greatest differences in adiposity between obese and non-obese children are predominately found in subcutaneous adipose tissue (353 ± 94 and 79 ± 61 cm2, respectively), rather than visceral adipose tissue (49 ± 21 and 22 ± 11 cm2, respectively).[30] A small retrospective paediatric study of 29 obese children showed that hepatic fat fraction correlated weakly (r = .37) with visceral adiposity measured with abdominal MRI.[31] Interestingly in our study, we found those children with radiological evidence of hepatic steatosis had greater abdominal subcutaneous adipose tissue than those without (32.0% vs 24.5%, P = 0.002), and the proportion of children with hepatic steatosis increased as subcutaneous adipose tissue increased (P < 0.01). In terms of visceral adipose tissue, we found it to be greater in older children with hepatic steatosis but not in those younger than 9.8 years. The precise role of abdominal visceral adiposity in children and progression of hepatic steatosis remains to be elucidated.

NAFLD is typically asymptomatic, and often diagnosis is made following an incidental finding of mildly elevated liver transaminases (particularly ALT) or imaging evidence of steatosis. The average ALT in our cohort in both males and females was mildly raised, approximately 40 U/L, which was unexpected, as we had excluded children with an intra-abdominal injury that may have been contributory to the elevation. Forty per cent of our subjects with hepatic steatosis had ALT levels twice the upper limit of normal, adjusted for sex. Elevated ALT values more than twice the upper limit of normal showed 40% sensitivity and 85% specificity in detecting children with hepatic steatosis. These findings are not unexpected, as it is known that ALT values can be normal in NAFLD, and do not correlate with histological findings and disease severity.[32,33]

In this study, we utilised contrast enhanced CT scans, which are not routinely performed to diagnose NAFLD in clinical practice. Hepatic steatosis lowers the attenuation of liver parenchyma. Unenhanced CT scans have been preferably performed to evaluate for steatosis, as contrast medium related factors, such as concentration, volume and rate and different vascularity of liver and spleen can potentially influence the hepatic attenuation and result in subtle differences in attenuation. However, recent evidence suggests that attenuation difference between liver and spleen on contrast enhanced portal venous phase CT and unenhanced CT scan have comparable accuracy in detecting hepatic steatosis.[34,35] A hepatic-splenic attenuation difference of −20 to −25 HU on portal venous phase images was found to have a sensitivity of 84%–87% and specificity of 75%–86% for the diagnosis of fatty infiltration,[17] suggesting our results accurately reflect the prevalence of hepatic steatosis. CT imaging can reliably determine both visceral adipose tissue and subcutaneous adipose tissue compartments.[15,36] Volumetric data based on multiple images provides the most complete assessment of abdominal adiposity, although associated with greater radiation exposure, and thus single slice method has been commonly adopted. Single slice at the level of the umbilicus is typically assessed to estimate abdominal adipose tissue content, and has been shown to provide good correlation with volumetric measurement.[37,38]

Limitations of this study include its retrospective nature that specifically limited our ability to obtain heights that would have allowed BMI calculations or access to data such as waist circumference. However, childhood obesity has a known subcutaneous adipose tissue pattern,[39] for example adolescent obese females have two to three times greater subcutaneous fat depots than non-obese.[40] As such, the greater proportion of abdominal subcutaneous adiposity in children and adolescents with hepatic steatosis is likely reflective of obesity. In addition, we did not have access to ethnicity data that could have enriched this report. It is likely our cohort is reflective of the general population, which in Ontario is highly diverse. The Canadian census statistics of 2016 reported 29.3% of the Ontario population to be of a visible minority with 29.6% being of South Asian origin, 19.4% Chinese, 16.2% Black and 8% Filipino.[41] While the Trauma Registry is at a single institution and may reflect the local NAFLD prevalence of an urban population, the Hospital for Sick Children is a major referral centre and one of two designated lead trauma hospitals for children, rendering it likely that our results are generalizable to the Province of Ontario. In this study, we did not have access to liver histology to confirm the diagnosis of NAFLD and to determine disease severity. Last, an additional limitation is the interpretation of ALT values in the context of a trauma in which enzyme release from myocytes may be increased, although we excluded patients with liver and other intra-abdominal injury.

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