Nonalcoholic Fatty Liver Disease in Children
Section snippets
Childhood obesity/overweight
Childhood obesity has become a major public health problem [1], [2], [3], [4]. Current estimates put the number of obese children at more than 20 million worldwide. Since the mid-1990s, the prevalence of overweight children in the United States has increased dramatically. Certain ethnic groups are particularly severely affected, with a 22% rise in African American children, 22% in Hispanic children, and 12% in non-Hispanic white children, according to 1998 data [1]. The same rise in childhood
Prevalence of childhood nonalcoholic fatty liver disease
It is difficult to determine the overall prevalence of childhood NAFLD. Most clinical reports suffer from defects of research design—mainly ascertainment bias—and therefore cannot address the question of disease prevalence. Relevant studies have examined the prevalence of fatty liver or abnormal serum aminotransferase levels in large, unselected groups of overweight or obese children. For technical reasons these studies tend to underestimate prevalence by failing to identify mild hepatic
Pathogenesis
Hyperinsulinemia, in association with insulin resistance, is now recognized as an essential component of the disease mechanism of NAFLD [49], [50], [51], [52], [53], [54]. In many adult patients, NAFLD seems to be the hepatic presentation of the metabolic syndrome. Increased concentrations of free fatty acids in plasma or in hepatocytes probably play an important role in the development of steatosis and inflammation [55], [56]. Insulin inhibits oxidation of free fatty acids, and thus
Hyperinsulinemia with insulin resistance in childhood nonalcoholic fatty liver disease
Accumulating data support the role of hyperinsulinemia with insulin resistance in childhood NAFLD [61], [62]. In a consecutive series of 43 children who had biopsy-proven NAFLD from San Diego, 95% met the criteria for insulin resistance when results for the homeostasis model of insulin resistance (HOMA-IR) and a related arithmetic estimate of insulin resistance (QUICK-I) were combined [61]. Children in this cohort were mostly male (70%), Hispanic American (53%), and obese (88%).
Adipocytokines
Adipose tissue acts as an endocrine tissue and produces metabolically active proteins (hormones or cytokines) known as adipocytokines. Those that modulate insulin action include tumor necrosis factor-α, adiponectin, and resistin. Adiponectin may play the most important role in the pathogenesis of NAFLD. Numerous studies indicate that obesity in children is associated with low concentrations of serum adiponectin [74], [75]. The severity of insulin resistance in obese children is inversely
Clinical findings in childhood nonalcoholic fatty liver disease
Numerous reports have provided an increasingly comprehensive description of NAFLD in children [51], [61], [66], [86], [87], [88], [89], [90], [91], [92], [93], [94]. Whereas NASH in adults was first described in the late 1970s, the first few case reports of childhood NASH appeared in the English language literature in the mid-1980s. The first large pediatric clinical series included 36 patients from various ethnic backgrounds collected prospectively and consecutively between 1985 and 1995 at
Liver histology in childhood nonalcoholic fatty liver disease
The diagnosis of NAFLD requires liver histology [100], [101], [102]. Some fat is expected to be present (involving at least 5% of the hepatocytes), except perhaps in advanced cirrhosis, which may appear to be cryptogenic [103], [104]. The fat globules may be small but are macrovesicular. When fat is present only as a bland lesion without inflammation, it is called simple steatosis. NASH implies the presence of inflammation, fibrosis, or both in addition to steatosis. The infiltrate consists of
Genetic/metabolic diseases associated with nonalcoholic fatty liver disease
Although hepatic steatosis in patients who have cystic fibrosis is probably caused different disease mechanisms from those operating in NAFLD, some genetic/metabolic diseases also involve hyperinsulinemia and hepatic insulin resistance and are characterized by chronic liver injury indistinguishable from NAFLD. Estimates of how many children who have NAFLD have cirrhosis do not include individuals who have these disorders and advanced liver damage. Bardet-Biedl and Alström syndromes are classic
Clinical approach to diagnosis of childhood nonalcoholic fatty liver disease
The typical patient who has childhood NAFLD is 10 to 14 years old, but patients may be as young as 4 to 5 years old. Most are overweight or obese by age- and gender-normative reference data. Those who are not overweight or obese are often tall for age and with weight on the same percentile as height, consistent with generalized overnutrition. Symptoms of liver disease are rare, but some children present with nonspecific abdominal pain. If serum aminotransferase levels are elevated, the overall
Treatment of childhood nonalcoholic fatty liver disease
Treatment currently consists of eliminating or reducing risk factors known to be associated with NAFLD. Comprehensive therapeutic studies are lacking in childhood NAFLD. Weight loss seems to improve the liver disease as judged by improvement in serum aminotransferase levels; histologic improvement has not been studied. Various pharmacologic interventions have been proposed, but few have been investigated rigorously.
Summary
NAFLD is an important liver disease in both adults and children. The entire range of liver involvement characterizing NAFLD can occur in children: hepatic macrovesicular steatosis without inflammation, steatosis with inflammation or fibrosis, and cirrhosis. NAFLD may occur in very young (preschool) children, with a male predominance among children and adolescents. If at all symptomatic, children often present with vague abdominal pain. NAFLD may be the hepatic manifestation of the metabolic
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This work was supported in part by the Canadian Association of Gastroenterology/Nestlé/CIHR Pediatric Nutrition Fellowship award (DRM) and the Metabolism Research Program/Mead-Johnson fund (to EAR).