Jim Kawakami, Nov 2, 2010, http://jimboguy.blogspot.com
William F. Balistreri, MD Oct 27, 2010 http://www.medscape.com/viewarticle/730873?src=mp&spon=17&uac=26057PR
I read that high-fructose corn syrup can induce or exacerbate fatty liver disease. What is the evidence?
Response from William F. Balistreri, MD
Dorothy M. M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Although the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex, increasing evidence suggests that fructose is a contributing factor. In the search for dietary triggers for NAFLD, fructose has been consistently identified as a candidate; this makes sense, given the metabolic events attendant to fructose ingestion. The digestion, absorption, and metabolism of fructose differ from those of glucose. Unlike glucose, fructose does not stimulate insulin secretion, enhance leptin production, or suppress hunger. Insulin and leptin are key afferent signals in the regulation of food intake and body weight; thus, dietary fructose may contribute to increased energy intake and weight gain. Hepatic metabolism of fructose has been shown to elicit potentially deleterious metabolic perturbations -- risk factors for NAFLD. Consumption of fructose-sweetened but not glucose-sweetened beverages increases fat mass, visceral adiposity, de novo lipogenesis, and inflammation, and it induces insulin resistance and postprandial hypertriglyceridemia, particularly in overweight individuals.[2-8]
The dietary goals to prevent the development of NAFLD or to forestall transition to nonalcoholic steatohepatitis (NASH) are to reduce adipose tissue mass and the associated inflammation, restore insulin sensitivity, and reduce de novo lipogenesis.[9,10] However, scientific evidence supporting specific diets or dietary restrictions is lacking. That said, a spate of recent investigations has identified overconsumption of high-fructose corn syrup, primarily in the form of soft drinks, as a modifiable risk factor/environmental exposure that increases the risk for NAFLD and the likelihood of progressing to NASH.[1,11]
Studies in Humans
The intake of simple carbohydrates is higher in patients with NAFLD compared with the general population, suggesting that this dietary imbalance plays a role in the development and progression of NAFLD.[6,11,12] A dietary history and paired serum and liver tissue samples were obtained from patients with biopsy-proven NAFLD without cirrhosis and control patients matched for sex, age, and body mass index. Consumption of fructose among patients with NAFLD was 3-fold higher than in controls. Abdelmalek and colleagues investigated the relationship between fructose consumption and disease severity in adults with NAFLD enrolled in the NASH Clinical Research Network. Increased fructose consumption was associated with younger age, male sex, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, increased calorie intake, and hyperuricemia. Daily fructose consumption was associated with increased hepatic inflammation and hepatocyte ballooning. Patients who drank the most fructose were more likely to have hepatic scarring and to progress to cirrhosis. These studies identify fructose as a readily modifiable environmental risk factor that can ameliorate disease progression in patients with NAFLD.
Studies in Animals
In animal models, ingestion of fructose (in contrast to glucose) causes fatty liver, along with development of leptin resistance and vascular inflammation.[13,14] A high-fructose diet induces changes similar to those seen in models of long-term alcohol intake and high-fat diets, including increased gut permeability, endotoxemia, increased hepatic tissue necrosis factor production, and hepatic steatosis. We hypothesized that mice exposed to a high-fructose diet would develop NASH with fibrosis associated with increased hepatic oxidative stress. Adult mice were randomly assigned to receive standard chow or high-fat, high-carbohydrate (HFHC) diets for 16 weeks; the HFHC group received water with 55% fructose and 45% sucrose. The HFHC group developed increased body weight and fat mass, became insulin-resistant, had elevated hepatic triglyceride and plasma alanine aminotransferase levels, and had a NASH-like phenotype with significant fibrosis. Hepatic oxidative stress was highest in HFHC-fed mice.
The mechanism of fibrosis might involve fructose inducing increased reactive oxygen species resulting in collagen deposition and histologically visible hepatic fibrosis. Spruss and colleagues have postulated another possible mechanism for fructose-induced hepatic steatosis in mice: the interaction between Toll-like receptor 4 and gut-derived endotoxins, such as lipopolysaccharide.
Fructose: A Marker or a Mediator?
Whether increased fructose consumption merely correlates with factors responsible for the development of NAFLD or directly promotes the transition from NAFLD to NASH and more advanced stages of liver damage remains unclear. Further research is needed, including well-designed prospective controlled dietary intervention studies to evaluate whether a low-fructose diet improves the metabolic disturbances associated with NAFLD and alters the natural history of NAFLD in those at risk for disease progression. These studies should also determine whether a threshold amount of fructose triggers the postulated adverse effects or if genetic susceptibility is responsible for these outcomes. In the interim, it seems prudent to reduce intake of fructose.
Subtract Added Sugars
Although long-term trials to study the effects of reducing the intake of fructose are needed, current data support dietary guidelines that target a reduction in consumption of all added sugar (caloric sweeteners used as ingredients in processed or prepared foods). Welch and colleagues tested the association between consumption of added sugars and adverse outcomes. A statistically significant correlation exists between excessive consumption of added sugars and several important measures of dyslipidemia, an important risk factor for NAFLD and cardiovascular disease. This, in turn, has been linked with several metabolic abnormalities and adverse health conditions, as well as shortfalls of essential nutrients. Although trial data are limited, evidence from observational studies indicates that a higher intake of added-sugar soft drinks is associated with greater energy intake, higher body weight, and lower intake of essential nutrients. On the basis of the 2005 US dietary guidelines, intake of added sugars greatly exceeds discretionary calorie allowances, regardless of energy needs; a mean of 16% of consumed calories was from added sugars. In view of these data, the American Heart Association has recommended reductions in the intake of added sugars. A prudent upper limit of intake is half of the discretionary calorie allowance, which for most women is no more than 100 calories per day and for most men is no more than 150 calories per day from added sugars.
We should consume less of all added sugars -- including fructose -- which are an increasing and potentially modifiable component of our diets. However, the makers of high-fructose corn syrup applied last month to the US Food and Drug Administration to change the name to "corn sugar" for use on food labels. "A rose by any other name will taste as sweet" -- thus, consumption will probably continue.