Recognition and Management of Children with Nonalcoholic Fatty Liver Disease

Serum Alanine Aminotransferase

Serum aminotransferases are one of the more common screening tests for NAFLD. However, ALT is highly insensitive at commonly used thresholds and is also nonspecific. As documented in the SAFETY study, the upper limit of normal for ALT in healthy children should be set around 25 U/L in boys and 22 U/L in girls [10]. Yet even at these thresholds, the sensitivity of ALT to diagnose NAFLD is 80% in boys and 92% in girls, whereas specificity is 79% and 85%, respectively [10]. These findings are largely consistent with adult studies [11–14]. Furthermore, ALT does not correlate well with disease severity and children may still have NASH or significant fibrosis with normal values. In a well-characterized cohort of 91 children with biopsy-proven NAFLD, for example, early fibrosis was identified in 12% of children with a normal ALT (≤ 22 U/L for girls and ≤ 25 U/L in boys) [15]. Advanced fibrosis or cirrhosis was seen in 9% of children with an ALT up to 2 times this upper limit [15]. Thus, reliance on the serum ALT may significantly underestimate the prevalence and severity of liver injury.

Ultrasonography

Children with NAFLD typically have findings of increased hepatic echogenicity on abdominal ultrasonography. However, there are multiple limitations to sonography. First, ultrasound is insensitive for identifying mild steatosis if less than 30% of hepatocytes are affected [16,17]. Second, increased hepatic echogenicity is nonspecific and may be caused by inflammation, fibrosis, or intrahepatic accumulation of iron, copper, or glycogen. Third, there can be considerable inter- and intra-operator variability. And lastly, there is some evidence that ultrasounds do not add benefit to diagnosing children with NAFLD [18].

• Which patients are at risk for developing hepatic steatosis and NASH?

Weight, Age, and Gender

There is a strong, direct correlation between body mass index (BMI) and NAFLD. The Study of Child and Adolescent Liver Epidemiology (SCALE)—a sentinel pediatric autopsy study of 742 children—found that 5% of normal weight children, 16% of overweight children, and 38% of obese children had NAFLD. The SCALE study also demonstrated an increasing prevalence with age, such that NAFLD was present in 17.3% of 15- to 19-year-olds but only in 0.2% of 2- to 4-year-olds [1]. With regards to gender, NAFLD is roughly twice as prevalent in males [18–20]. While the exact etiology of this difference is unclear, hormonal differences are a leading hypothesis.

Ethnicity

NAFLD is most common in Hispanics, followed by Asians, Caucasians, and African Americans. Research suggests that genetics may be largely responsible for these ethnic disparities. For example, the I148M allele of PNPLA3 (a single nucleotide polymorphism) is strongly associated with steatosis, NASH, and fibrosis [21] and is most common in Hispanics, with a 50% carrier frequency in some cohorts [22]. Conversely, African Americans are more likely to carry the S453I allele of PNPLA3, which is associated with decreased hepatic steatosis [22]. There is also considerable variability within ethnic groups. For example, Mexican-American children appear to be at the highest risk for steatosis or NASH among Hispanics, whereas Filipino-American children are believed to have higher disease prevalence than Cambodian or Vietnamese Americans [1].