ReviewPediatric nonalcoholic fatty liver disease (NAFLD): A “growing” problem?
Introduction
Children today are in an unprecedented predicament nutritionally. Food is plentiful, and yet an increasing number of children suffer from suboptimal nutrition: they are overweight or obese. The adverse consequences of childhood overweight/obesity are no longer simply psychological. They include hyperlipidemia, hypertension, type 2 diabetes mellitus, sleep apnea, degenerative joint disease, and chronic renal dysfunction. For an increasing number of children worldwide, nonalcoholic fatty liver disease (NAFLD) can be added to this list. NAFLD is a liver disease spectrum consisting of simple steatosis (SS; macrovesicular steatosis in hepatocytes without inflammation), nonalcoholic steatohepatitis (NASH; macrovesicular steatosis in hepatocytes associated with inflammation and fibrosis), and cirrhosis. NASH was first described in adults in the late 1970s; it was first reported in children in the early 1980s. Only 25 years later, NAFLD is recognized as highly prevalent in both adults and children. Because childhood obesity is a growing problem, pediatric NAFLD is rapidly becoming one of the most important chronic liver diseases in children. Thus, pediatric NAFLD is a growing problem. Increased attention to this disease and rapidly escalating rates of actually making the diagnosis certainly contribute to the impression that pediatric NAFLD is ballooning out of control.
The importance of pediatric NAFLD extends beyond the likely increased burden of serious chronic liver disease as children with NAFLD reach adulthood. From the theoretical standpoint, examining NAFLD in children has provided important clues to the nature of the disease itself. In the early 1980s when it was not universally accepted that the disease nonalcoholic steatohepatitis actually existed in adults, detection of NASH in children provided cogent evidence in favor of a “new” liver disease. The stereotypic female predominance in adult NASH was questioned when boys repeatedly outnumbered girls in initial clinical series of pediatric NAFLD. The pivotal role of hyperinsulinemia was apparent in children who had acanthosis nigricans or in those children with congenital metabolic disorders characterized by insulin resistance due to insulin receptor abnormalities. The prominent difference between children and adults is that children are actively growing. This review compares and contrasts pediatric and adult NAFLD and points out sentinel features of pediatric NAFLD.
Section snippets
Childhood overweight/obesity
In the past two decades prevalence of childhood overweight/obesity has increased worldwide. In children the normal range for body mass index (BMI) varies with age. The merits and subtleties of BMI determinations in children have been reviewed [1]. A recent estimate for worldwide incidence was that 7–8% of children and adolescents in the 5–17-year-old age-bracket are overweight and 2–3% obese. Worldwide burden of childhood overweight/obesity was estimated at 150 million for the year 2000 [2].
Pediatric NAFLD
Pediatric NAFLD was first reported in the mid-1980s. Large clinical series appeared only recently. The first reports described mainly NASH [20], [21], and the distinction between SS and NASH is not always evident. The Toronto series was the first large prospective clinical series [22]. Males predominated, age-range was 4–16-years-old at diagnosis, and weights were 114–192% of ideal weight-for-height. Liver biopsy, performed in 24 of the 36 patients, showed that 71% had some fibrosis and a
Pediatric NAFLD with hypothalamic disorders
Hypothalamic disorders predispose to pediatric NAFLD. Children with hypothalamic dysfunction, congenital or acquired, as occurs after resection of craniopharyngioma, may be hyperphagic and experience severe, rapid weight gain. They are at risk for rapid development of cirrhosis [27], [28], [29], [30], [31], [32], [33]. Some have the metabolic syndrome [34]. NAFLD has been found in patients with Prader–Willi syndrome (PWS), disorder of imprinting affecting the hypothalamus [28], [35].
Pediatric NAFLD with genetic/metabolic disease
Classification of fatty liver disease (macrovesicular steatosis) finds its first branch-point at ‘alcoholic’ versus ‘nonalcoholic’ disease. For children, the ‘nonalcoholic’ domain is more important than the ‘alcoholic’ (Table 1). A further distinction is between disease associated with the insulin resistance syndrome as such (that is, NAFLD) and fatty liver disease associated with inherited metabolic disorders, most of which exhibit insulin resistance on a structural or biochemical basis.
Histology of pediatric NAFLD
In both children and adults the strict diagnosis of NAFLD requires liver histology [31], [52]. SS, the most prevalent form of pediatric NAFLD, is not necessarily benign. Steatosis may be minimal in cirrhosis associated with NAFLD. Although cryptogenic cirrhosis in adults is often due to NAFLD [53], [54], this is probably not yet the case in children: unapparent chronic inflammatory disease, such as primary sclerosing cholangitis, should be sought.
An important difference between adult and
Disease mechanism in pediatric NAFLD
At the present time, hepatic insulin resistance is regarded as essential to the disease mechanism in NAFLD. Although determinants predisposing to pediatric NAFLD may differ from those operating in adults, hyperinsulinemia with hepatic insulin resistance is an important feature of pediatric NAFLD. In all age-brackets, most affected individuals develop overweight/obesity and then fatty liver [58]. The mechanistic pathways between increased body weight and fatty liver are complex. Increased
Natural history of pediatric NAFLD
In adults NAFLD appears to be a slowly progressive liver disease with a definable risk of adverse outcomes, such as cirrhosis [99]. The natural history of pediatric NAFLD remains uncertain. A broad cross-sectional study in California looked at NAFLD in children who died accidentally and were subject to examination by the coroner [85] found that fatty liver was present in 13% of 742 children studied. Steatohepatitis was found in 23% of those with fatty liver, and severe fibrosis or cirrhosis was
Diagnosis of pediatric NAFLD
Typical clinical findings, associated diseases, and diagnostic approaches have recently been reviewed critically [102]. The typical child with NAFLD is 11–13-years-old, usually male, usually overweight or obese. Some children with NAFLD are tall and proportionally heavy, consistent with being overnourished. In each series approximately 10% do not meet anthropometric definitions for overweight or obesity. Most children with NAFLD are asymptomatic. Some have vague abdominal pain. Physical
Treatment of pediatric NAFLD
The first step in treating pediatric NAFLD is to identify it. For many parents and physicians this entails accepting that pediatric obesity is a medical problem. Recent clinical studies suggest that this initial step is difficult [103], [104]. Besides height and weight, measuring waist circumference provides highly informative data [105], [106]. Waist circumference is a surrogate for visceral adiposity, shown in a small study to predispose to pediatric NAFLD [107], as in adults [108], [109]. To
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