Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease

Abstract

The rising incidence of obesity and diabetes coincides with a marked increase in fructose consumption. Fructose consumption is higher in individuals with nonalcoholic fatty liver disease (NAFLD) than in age-matched and body mass index (BMI)-matched controls. Because fructose elicits metabolic perturbations that may be hepatotoxic, we investigated the relationship between fructose consumption and disease severity in NAFLD. We studied 427 adults enrolled in the NASH Clinical Research Network for whom Block food questionnaire data were collected within 3 months of a liver biopsy. Fructose consumption was estimated based on reporting (frequency x amount) of Kool-aid, fruit juices, and nondietary soda intake, expressed as servings per week, and classified into none, minimum to moderate (<7 servings/week), and daily (> or =7 servings/week). The association of fructose intake with metabolic and histological features of NAFLD was analyzed using multiple linear and ordinal logistic regression analyses with and without controlling for other confounding factors. Increased fructose consumption was univariately associated with decreased age (P < 0.0001), male sex (P < 0.0001), hypertriglyceridemia (P < 0.04), low high-density lipoprotein (HDL) cholesterol (<0.0001), decreased serum glucose (P < 0.001), increased calorie intake (P < 0.0001), and hyperuricemia (P < 0.0001). After controlling for age, sex, BMI, and total calorie intake, daily fructose consumption was associated with lower steatosis grade and higher fibrosis stage (P < 0.05 for each). In older adults (age > or = 48 years), daily fructose consumption was associated with increased hepatic inflammation (P < 0.05) and hepatocyte ballooning (P = 0.05).

Conclusion: In patients with NAFLD, daily fructose ingestion is associated with reduced hepatic steatosis but increased fibrosis. These results identify a readily modifiable environmental risk factor that may ameliorate disease progression in patients with NAFLD.

Figure 1

Fructose Associated Hepatic ATP Depletion For each fructose molecule that is metabolized, two molecules of ATP are consumed.. The resultant ADP is then further degraded to AMP. The fate of this AMP is dictated by the relative activities of two competing enzymes, AMP kinase (AMPK) and xanthine dehydrogenase. When AMPK is more active than xanthine dehydrogenase, AMP is “re-cycled” to restore hepatocyte ATP content. Conversely, when xanthine dehydrogenase is more active than AMPK, AMP is converted to uric acid, delaying recovery of hepatic ATP stores. Insulin resistance, which decreases AMPK activity, further augments the effect of fructose metabolism, resulting in hepatic ATP depletion.