June 30, 2008 — Nonalcoholic fatty liver disease (NAFLD) in overweight and obese children is strongly associated with several cardiovascular risk factors, according to the results of a case control study reported in the June 30 Online First issue and will appear in the July 8 issue of Circulation.

"NAFLD, the most common cause of liver disease in children, is associated with obesity and insulin resistance," write Jeffrey B. Schwimmer, MD, from the University of California–San Diego, and colleagues. "However, the relationship between NAFLD and cardiovascular risk factors in children is not fully understood."

The goal of this study was to evaluate the association between NAFLD and metabolic syndrome in overweight and obese children. Rates of metabolic syndrome with use of Adult Treatment Panel III criteria were compared for 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD, matched for age, sex, and degree of obesity.

Compared with overweight children without NAFLD, those with NAFLD had significantly higher fasting glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. They also had higher systolic and diastolic blood pressures as well as significantly lower high-density lipoprotein (HDL) cholesterol levels.

Children with metabolic syndrome had 5-fold the risk of having NAFLD as those without metabolic syndrome after adjustment for age, sex, race, ethnicity, body mass index (BMI), and hyperinsulinemia (odds ratio, 5.0; 95% confidence interval, 2.6 - 9.7).

"NAFLD in overweight and obese children is strongly associated with multiple cardiovascular risk factors," the study authors write. "The identification of NAFLD in a child should prompt global counseling to address nutrition, physical activity, and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes."

Limitations of this study include likely misclassification of some subjects having NAFLD as normal controls; cross-sectional design allowing only association rather than causation; the possibility that some difference in insulin sensitivity between cases and controls could have been attributable to differences in Tanner stage; unclear generalizability to overweight black children, because they are known to have high rates of diabetes yet low rates of NAFLD; and inability to resolve many issues regarding the definition and significance of metabolic syndrome in children and adolescents.

"These data should be used to increase awareness of this subset of overweight and obese children and to guide future studies aimed at elucidating natural history and treatment," the study authors conclude. "Such studies will help to further define the role of fatty liver as a marker or possible mediator of risk for cardiovascular events."

The Rest Haven Foundation; the National Institute of Diabetes, Digestive and Kidney Diseases; the National Center for Research Resources of the National Institutes of Health for the General Clinical Research Center at the University of California—San Diego; and the National Heart, Lung, and Blood Institute supported this study in part. The study authors have disclosed no relevant financial relationships.

Circulation. Published online June 30, 2008.

Clinical Context

Study Highlights

• 300 overweight or obese children aged 5 to 17 years referred to a pediatric gastroenterology clinic for obesity or possible NAFLD were enrolled.
• All children were overweight, defined by a BMI between the 85th and 94th percentiles.
• 96% were obese, defined as a BMI above the 95th percentile.
• Male and female subjects were matched 1:1 in case and control groups.
• 150 case subjects had NAFLD defined by at least 5% hepatocytes containing macrovesicular fat on liver biopsy and exclusion of other chronic liver disease, including hepatitis B, hepatitis C, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, drug toxicity, total parenteral nutrition, and chronic alcohol intake.
• 150 control subjects had absence of NAFLD defined by normal alanine aminotransferase and aspartate aminotransferase levels (< 30 U/L) and no hepatomegaly.
• NAFLD and control groups were similar in age (mean, 12.7 years), severity of obesity, and BMI z score.
• NAFLD vs control group had fewer black (4% vs 21%), fewer white (20% vs 30%), more Hispanic (66% vs 45%), and more Asian subjects.
• Physical examination measurements included height, weight, waist circumference, systolic blood pressure, and diastolic blood pressure.
• 12-hour fasting laboratory tests included glucose levels, insulin levels, total, HDL, and LDL cholesterol levels; triglyceride levels; and alanine aminotransferase and aspartate aminotransferase levels.
• Metabolic syndrome diagnosis was based on at least 3 of 5 findings: abdominal obesity (waist circumference > 102 cm in boys and > 88 cm in girls), high triglyceride levels (at least 150 mg/dL), low HDL cholesterol levels (< 40 mg/dL for boys and < 50 mg/dL for girls), elevated blood pressure (systolic pressure at least 135 mm Hg and diastolic pressure at least 85 mm Hg), and high fasting glucose level (at least 100 mg/dL).
• For absolute values of cardiovascular risk factors, the NAFLD vs control group had higher glucose, insulin, and homeostasis model assessment of insulin resistance levels; higher systolic and diastolic blood pressures; higher total cholesterol, LDL cholesterol, and triglyceride levels; lower HDL cholesterol levels; and no significant difference in waist circumference.
• All children with NAFLD had at least 1 metabolic syndrome finding.
• NAFLD vs control group had more metabolic syndrome features.
• Metabolic syndrome was more common in NAFLD vs control group (50% vs 15%; P < .001).
• Metabolic factors were more likely to be abnormal for NAFLD vs control group:
  • Abdominal obesity, 74% vs 60%; P = .010
  • High total cholesterol levels (at least 200 mg/dL), 26% vs 14%; P = .009
  • High LDL cholesterol levels, (at least 130 mg/dL), 23% vs 13%; P = .016
  • Low HDL cholesterol levels, 72% vs 55%; P = .002
  • High triglyceride levels, 46% vs 12%; P < .001
  • Elevated blood pressure, 32% vs 16%; P = .001
  • High glucose levels, 19% vs 3%; P < .001
• Children with metabolic syndrome vs without metabolic syndrome were more likely to have NAFLD (odds ratio, 5.0; 95% confidence interval, 2.6 - 9.7; P < .001), after adjustment for age, sex, race, ethnicity, BMI, and hyperinsulinemia (insulin at least 20 U).
• Study limitations included possible misclassification of control subjects, cross-sectional design, lack of data on timing of metabolic syndrome development, and inability to generalize results to all ethnic groups.

Pearls for Practice

• Overweight children with NAFLD vs without NAFLD are more likely to have metabolic syndrome and metabolic factors of central obesity, elevated total cholesterol levels, elevated LDL cholesterol levels, elevated triglyceride levels, low HDL cholesterol levels, elevated blood pressure, and impaired fasting glucose.
• Overweight children with metabolic syndrome vs overweight children without metabolic syndrome have 5-fold increased odds of NAFLD.

CME Test