We performed a case-control study in a large clinical sample of overweight and obese children and adolescents with and without NAFLD. Children with biopsy-proven NAFLD had higher absolute values of cardiovascular risk markers and were more likely to exceed dichotomous thresholds for increased cardiovascular risk. In addition, after controlling for established demographic and biological risk factors, we found that overweight and obese children with metabolic syndrome had greater odds of having NAFLD than overweight and obese children without metabolic syndrome.
These data substantially extend the knowledge base of metabolic syndrome in children with NAFLD. In a cross-sectional analysis of adolescents in the Korean National Health and Nutrition Examination Survey, the odds of having abnormal serum alanine aminotransferase activity were increased by the presence of central obesity, elevated serum triglycerides, or low HDL cholesterol levels.28
In a substudy of 72 obese adolescents seen at the Yale Pediatric Obesity Clinic, 14 of 23 subjects with fatty liver detected by magnetic resonance imaging met modified adolescent criteria for metabolic syndrome.22
In contrast, only 11 of 49 subjects with a hepatic fat fraction <5.5% met the modified criteria for metabolic syndrome. The present study demonstrates that obese children and adolescents with a definitive diagnosis of NAFLD have a more severe cardiovascular risk profile than age-, sex-, and BMI-matched peers. In adults, hepatic steatosis has been shown to be associated with hepatic insulin resistance and features of metabolic syndrome independently of the amount of visceral adipose tissue.29,30
Taken together, these data illustrate that fat accumulation in the liver may play a more important role than obesity itself in determining the risk for “weight-related” metabolic comorbidities. Thus, in children and adolescents, NAFLD may serve as a marker to stratify the cardiovascular risk of overweight and obese patients.
In a study of Japanese university students ≈8 years older than our study population, those with liver ultrasonography consistent with fatty liver had increased arterial stiffness as measured by ankle brachial pulse-wave velocity compared with students without evidence of fatty liver.31
Similarly, in young obese Italian children, those with liver ultrasonography consistent with fatty liver had greater carotid artery intima-media thickness than those with normal liver ultrasonography.32
The belief that NAFLD is associated with cardiovascular disease is further supported by epidemiological data on cardiovascular morbidity in adults. Among 129 adults with biopsy-proven NAFLD, survival was lower than in a matched reference population mainly because of higher mortality from cardiovascular disease.33
Targher and colleagues34
observed that adults with type 2 diabetes and ultrasound evidence of NAFLD had a significantly increased incidence of cardiovascular events compared with controls with diabetes and without NAFLD. Thus, we believe that children with NAFLD are likely to be a high-risk group for future cardiovascular events, but it remains to be determined whether NAFLD or metabolic syndrome confers additional risk beyond traditional cardiovascular risk factors.
The identification of NAFLD in a child should prompt consideration of cardiovascular health. Global counseling should address nutrition, physical activity, and avoidance of smoking. There are insufficient data on the use of medications in this population. However, there are many potential targets for medication, and future studies need to address the desirability of addressing individual problems such as hypertension pharmacologically versus targeting a broader issue such as obesity or insulin resistance. Many children with NAFLD, if unable to achieve sufficient improvement via lifestyle modification, will likely receive pharmacotherapy for such comorbidities as hypertension or dyslipidemia. However, it is not clear whether these treatments have a beneficial, neutral, or deleterious effect on the natural history of NAFLD.
Fatty liver also may prove to be a mediator of metabolic syndrome. In the liver, fatty acids may be either oxidized or esterified to form triglycerides, which are then either stored in the cytosol or secreted in very-low-density lipoprotein.35
The intracellular triglyceride storage depot likely serves as a temporary buffer for potentially toxic free fatty acids when their delivery to the liver exceeds its oxidative and very-low-density lipoprotein secretory capacity.36
The expanded liver fatty acid pool leads to increased mitochondrial and peroxisomal β-oxidation, which produces reactive oxygen species. This may, in turn, promote both a local proinflammatory state leading to progressive liver injury and the release of proinflammatory cytokines, which stimulate production of suppressors of cytokine signaling proteins. An increase in suppressors of cytokine signaling-3 in the liver leads to persistent hyperinsulinemia, which further exacerbates insulin resistance.37
Hyperinsulinemia stimulates the transcription factor sterol regulatory element-binding protein-1c,38
which leads to activation of lipogenic genes and a decrease in fatty oxidation. Additional overproduction of fatty acid and continued lipotoxicity result in further insulin resistance, creating a vicious cycle. Fatty liver also leads to hepatic insulin resistance by stimulating gluconeogenesis and activating protein kinase C and Jun N-terminal kinase 1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.39
Thus, fatty liver contributes to the dysregulation of both glucose and lipid metabolism.
The development of NAFLD in children may precede the development of type 2 diabetes mellitus. At the time of diagnosis, ≈8% to 10% of children with NAFLD have diabetes.5,40
In contrast, by the time type 2 diabetes mellitus is diagnosed in children, approximately one half have suspected fatty liver because of elevated alanine aminotransferase.41
Hepatocyte triglyceride storage causes acquired insulin signaling defects, leading to insulin resistance, glucose intolerance, and type 2 diabetes mellitus.42
The high rates of overweight, insulin-resistant children with NAFLD meeting the criteria for metabolic syndrome suggest that a large number of these children will go on to develop diabetes. This belief is supported by a cohort study from Sweden of adults with biopsy-proven NAFLD who had a 9% prevalence of diabetes at baseline.33
After nearly 14 years of follow-up, the majority (78%) of these patients developed impaired glucose tolerance or diabetes.
The strengths of the present study were the large series of biopsy-proven pediatric NAFLD and the use of a control group that was well matched for age, gender, and severity of obesity. The control group met a clinically accepted standard for the absence of NAFLD. The limitations of the study included the likely misclassification of some subjects having NAFLD as normal controls. We conducted sensitivity analyses to account for misclassification rates of 10% and 20% and found that the association between metabolic syndrome and NAFLD remained strong. The cross-sectional nature of the study allowed only association rather than causation. Moreover, these data cannot be used to determine the timing of development of metabolic syndrome in children with NAFLD. Although subjects were well matched for gender and age, it is possible that some difference in insulin sensitivity between cases and controls could have been attributable to differences in Tanner stage, which was not assessed. In addition, it is not clear to what extent these data are generalizable to overweight black children because they are known to have high rates of diabetes yet low rates of NAFLD.1,43
Finally, many issues regarding the definition and significance of metabolic syndrome in children and adolescents remain unresolved. The true risk of pediatric NAFLD for cardiovascular events can be determined only by long-term longitudinal cohort studies with detailed baseline characterization and clinically relevant end points.