Management of nonalcoholic fatty liver disease in children

Authors

  • Jean P. Molleston

    Corresponding author
    1. Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN
    • Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, 702 Barnhill Drive, Room ROC 4210, Indianapolis, IN 46202. E-mail: jpmolles@iupui.edu

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  • Potential conflict of interest: Nothing to report.

Abstract

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Abbreviations
ALT

alanine aminotransferase

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of hepatic fat in individuals without a history of excessive alcohol consumption. The term nonalcoholic steatohepatitis (NASH) is used when inflammation and liver injury are seen on liver biopsy in patients with NAFLD. Fatty liver is the most common cause of liver disease in children. Epidemiological data from the National Health and Nutrition Examination Survey III estimated a prevalence of NAFLD of 3% in adolescents with elevated ALT as a criterion.[1] An autopsy study indicated an NAFLD prevalence of nearly 10%; this prevalence increased to 38% in obese teens.[2] Pediatric NAFLD is diagnosed most commonly in the early teenage years, although it has been described much earlier in childhood. NAFLD is more prevalent in boys. Hispanics are more likely to have NAFLD than Caucasians, whereas African Americans are the least affected group. Although obesity is overwhelmingly the most common cause of NAFLD, cystic fibrosis, mitochondrial disorders, or metabolic liver disease also can cause NAFLD, albeit with different pathophysiological and epidemiological features.

The pathogenesis of NAFLD is not completely clear. Hepatic fat accumulation and insulin resistance, typically in the context of obesity, play an important role. Other pathophysiological factors, including oxidative stress, cytokine-mediated injury, and increased fibrogenesis, may contribute to the development of significant liver disease.[3]

Pediatric data regarding the natural history of NAFLD are limited. Kohli et al.[4] described progression of fibrosis in 3 to 5 years in 2 children with NAFLD. In a retrospective study of 66 children with NAFLD with a 20-year follow-up, 4 children demonstrated diabetes, 2 died, and 2 underwent transplantation. Of 5 who underwent multiple biopsies, 4 demonstrated progression of fibrosis.[5] Cirrhosis in childhood NASH has been described, although it is rare.[6]

Approaches to screening for NAFLD in children are controversial. Clearly, obese children are at the highest risk. Ultrasound, which may detect hepatic steatosis in up to three-quarters of obese children, is not a practical screening tool. An American Academy of Pediatrics expert committee has recommended biannual screening with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in obese children older than 10 years and in overweight children with risk factors.[7] Further study is needed to provide evidence for the optimal screening strategy.

The evaluation for NAFLD can include biochemical, radiographic, and histological studies. Although mildly elevated ALT (with ALT > AST) is typical in pediatric and adult NAFLD patients, liver enzymes may correlate poorly with disease activity. Blood tests should be carried out to evaluate patients for other causes of liver disease, including Wilson's disease (which can cause fatty liver), viral hepatitis, alpha-1-antitrypsin deficiency, and autoimmune hepatitis. It is notable, however, that low titers of autoantibodies can be seen in pediatric NAFLD.[5] In children with NAFLD who are not obese or who are very young, evaluations for metabolic liver diseases, such as mitochondrial, peroxisomal, and lysosomal disorders, may be indicated. Ultrasound detects many cases of NAFLD but cannot address inflammation, cell injury, or fibrosis. Magnetic resonance imaging, especially with spectroscopy, is more accurate but is expensive and difficult. Liver biopsy is the gold standard for the diagnosis of NAFLD. Although some children display the typical adult pattern of steatosis with ballooning degeneration and perisinusoidal fibrosis, up to half of children with NASH display steatosis with portal inflammation and fibrosis but little ballooning.[9] Liver biopsy is useful to clarify the diagnosis when another cause of liver disease such as autoimmune hepatitis is being considered, to gauge the severity of the liver disease, and before the initiation of drug therapy.

The first approach to the management of pediatric NAFLD is recommending a diet and exercise program. These lifestyle changes can affect the metabolic changes associated with NAFLD. Children should limit the consumption of sweetened beverages and should consume a balanced diet low in energy-dense foods and rich in fruits and vegetables. So-called screen time should be limited, and at least 1 hour of aerobic exercise per day is recommended. There is some (limited) evidence that lifestyle changes can lead to improved ALT levels, improved steatosis on ultrasound, and even histological improvement.[10] Such interventions are important to address underlying obesity and its attendant future risks. Pediatric studies of ursodeoxycholic acid and insulin sensitizers in general have not shown benefits in NAFLD, whereas there have been some mildly encouraging data concerning vitamin E.[11] A large randomized controlled trial recently compared metformin, vitamin E, and a placebo in children with NAFLD. Metformin was not better than the placebo in attaining the ALT endpoint.[12] Although vitamin E was not superior to the placebo in improving ALT levels, histological improvement was seen in a subset of patients with NASH. More studies are needed. Other important aspects in the care of children with chronic liver disease include immunization against hepatitis A and B and counseling to avoid potential hepatotoxins such as alcohol.

Future studies in pediatric NAFLD will need to begin by elucidating the underlying pathophysiological features of the disease. Identifying noninvasive biomarkers for NASH activity will be important. Clinical trials will need to address the usefulness of drug therapy—antioxidant, anti-inflammatory, antifibrotic, or other—in addition to lifestyle modifications.

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