Recognition and Management of Children with Nonalcoholic Fatty Liver Disease

From the Albert Einstein College of Medicine, Division of Pediatric Gastroenterology and Nutrition, Children’s Hospital at Montefiore, Bronx, NY.

Abstract

• Objective: To review diagnostic challenges and management strategies in children with nonalcoholic fatty liver disease (NAFLD).
• Methods: Review of the literaure.
• Results: NAFLD is common in the United States and should be suspected in overweight or obese children with an elevated serum alanine aminotransferase level. The differential diagnosis for these patients is broad, however, and liver biopsy—the gold standard test—should be undertaken selectively after an appropriate workup. Patients should be counseled on lifestyle modifications, whereas vitamin E therapy can be initiated for those with biopsy-proven disease.
• Conclusion: Providers should have a high degree of suspicion for NAFLD, approaching the workup and diagnosis in an incremental, step-wise fashion. Further research is needed to standardize the diagnostic approach, identify reliable, noninvasive diagnostic measures, and develop novel treatment modalities.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, affecting approximately 10% of children and a third of all adults in the United States [1–3]. It is a significant public health challenge and is estimated to soon be the number one indication for liver transplantation in adults.

NAFLD is a generic term encompassing 2 distinct conditions defined by their histopathology: simple steatosis and nonalcoholic steatohepatitis (NASH). Simple steatosis is characterized by predominantly macrovesicular—meaning large droplet—cytoplasmic lipid inclusions found in ≥ 5% of hepatocytes. NASH is defined as hepatic steatosis plus the additional features of inflammation, hepatocyte ballooning, and/or fibrosis. There are some adult data [4-6] and 1 retrospective pediatric study [7] demonstrating that over time, NAFLD may progress. That is, steatosis may progress to NASH and some patients with fibrosis will ultimately develop cirrhosis. If intervention is provided early in the histologic spectrum, NAFLD can be reversed [4,8] and late complications—such as cirrhosis, hepatocellular carcinoma, or liver transplantation—may be prevented.

It is important to highlight that the above definitions are based on histology and that a liver biopsy cannot be reasonably obtained in such a large percentage of the U.S. population. This case-based review will therefore focus primarily on the current diagnostic challenges facing health care providers as well as management strategies in children with presumed NAFLD.

Case Study

Initial Presentation

As you finish your charts at the end of a busy clinic day, you identify 3 patients who may have NAFLD:

History

All 3 patients presented to your office for a routine annual physical before the start of the school year and are asymptomatic. None of the patients has a family history of liver disease and their previously diagnosed comorbidities are listed in the table above. No patient is taking medications other than patient C, who is on metformin.

All 3 children have a smooth, velvety rash on their necks consistent with acanthosis nigricans with an otherwise normal physical exam. The liver and spleen are difficult to palpate but are seemingly normal.

• What is the typical presentation for a child with NAFLD?

Most children with NAFLD are asymptomatic, though some may present with vague right upper quadrant abdominal pain. It is unclear, however, if the pain is caused by NAFLD or is rather an unrelated symptom that brings the child to the attention of a physician. In addition, hepatomegaly can be found in over 30% to 40% of patients [9]. For children without abdominal pain or hepatomegaly, most are recognized by an elevated serum alanine aminotransferase (ALT) or findings of increased liver echogenicity on ultrasonography.

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.