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1 From the Clinical Nutrition and Risk Factor Modification Center (DJAJ, ARJ, LSAA, and CWCK) and the Division of Endocrinology and Metabolism (DJAJ), St. Michael's Hospital, Toronto, Canada; and the Departments of Nutritional Sciences (DJAJ,ARJ, RL, AM, LSAA, and CWCK) and Medicine (DJAJ), Faculty of Medicine, University of Toronto, Toronto, Canada
See corresponding article on page 136.
As the incidence of obesity in adults and children increases, so does the incidence of fatty liver disease. It has been estimated that 20% of adults have excess fat in the liver—ie, they have nonalcoholic fatty liver (NAFL). Of these persons, 10%–15% are likely to develop nonalcoholic steatohepatitis (NASH). Serum liver concentrations of enzyme alanine transaminase (ALT) >30 IU in men and >19 IU in women should increase the level of suspicion of NASH (1), and an aspartate transaminase (AST)-to-ALT ratio of >0.9 may progressively be associated with increased fibrosis (2). Cirrhosis develops in 20% of persons with NASH, and, of that group, 30%–40% will die of end-stage liver disease (3).
NAFL is one of the disorders of ectopic fat storage that has a strong association with insulin resistance. Fat is stored in hepatocytes and muscle fibers (intramyocellular fat), rather than in adipocytes. In addition to its common occurrence in obesity, NAFL is found in an extreme form in persons with lipodystrophy. Its frequency is increased by inactivity, and it is relatively common in persons with type 2 diabetes. Other than weight loss, effective treatment strategies for NAFL are not yet available. The administration of ursodeoxycholic acid to treat the inflammatory aspect has proven ineffective. Regular exercise, which reduces insulin resistance, has been shown in small trials to improve NAFL, but effective weight-loss trials are still required. Bariatric Roux-en-y gastric bypass surgery that leads to weight loss in the severely obese has been shown to be effective, as have therapies to increase insulin sensitivity, such as the use of thiazolidinediones (4) or of leptin (5) in generalized lypodystrophy. Through the redistribution of ectopic fat to adipose tissue, adiponectin, a peroxisome proliferator–activated receptor– agonist, would also be predicted to work (6), but it has not been tested. Metformin was shown to improve liver enzymes but not liver fat in diabetes patients (7).
The article by Valtueña et al (8) in the current issue of the Journal offers an additional strategy for both preventing and treating NAFL and NASH and is therefore timely. The authors have assessed the effects of both the quality and the quantity of carbohydrate as drivers of hepatic de novo lipogenesis. A cross-sectional study of 247 healthy subjects with no identified medical conditions was carried out in the Parma area of Northern Italy. Intakes of total carbohydrate and fiber, glycemic index (GI), and glycemic load were measured from a semiquantitative food-frequency questionnaire.
The study focused on the dietary correlations with NAFL. The prevalence of high-grade fatty liver, diagnosed by ultrasound, increased significantly across quartiles of dietary GI: in the highest quartile, the prevalence was twice that in the other 3 quartiles. However, in a subgroup of subjects who were insulin sensitive [lower 3 quartiles of homeostasis model assessment of insulin resistance (HOMA-IR)], no difference was seen in the prevalence of high-grade hepatic steatosis between those consuming a high-GI diet and those consuming a low- or medium-GI diet, which indicated that the GI was a factor in NAFL only in insulin-resistant subjects. Total carbohydrate, glycemic load, and dietary fiber were not related to NAFL.
The implication of this study is that a low-GI diet, or selection of lower-GI rather than higher-GI foods, may benefit persons with NAFL. The low-GI foods in the study by Valtueña et al included pasta, rice, corn, dairy products, and fruit, and the high-GI foods were bread, pizza, and savory snacks. It remains to be seen whether a dietary change to emphasize these low-GI foods either alone or with various combinations of exercise, weight loss, or the peroxisome proliferator–activated receptor– agonists such as thiazolodinediones proves effective and so becomes part of an established treatment for NAFL.
As the authors point out, recent studies suggest that de novo lipid synthesis accounts for 26% of the liver lipid, whereas 59% comes from free fatty acid (FFA) liberated from peripheral adipose tissue and 15% comes from dietary lipid. Factors that increase hepatic de novo lipogenesis or control the release of FFA from adipose tissue stores are therefore likely to play a role in the generation of fatty liver. Central adiposity as part of the metabolic syndrome is associated with greater amounts of intraabdominal fat and potentially higher portal venous FFA concentrations. In addition to increasing hepatic lipid synthesis, high portal venous FFA concentrations have been shown to reduce the hepatic clearance of insulin (9, 10) and thus to raise insulin concentrations in the peripheral circulation and to down-regulate peripheral insulin receptors (11). One can speculate that the hyperinsulinemia of insulin resistance will be further exacerbated by high-GI foods that require the mobilization of large amounts of insulin, which will further down-regulate peripheral insulin receptors and increase insulin resistance. As liver disease progresses to cirrhosis, hepatic extraction of insulin is further reduced by intrahepatic and extrahepatic shunting of portal venous blood directly into the systemic circulation. At the same time, low bile acid concentrations in the lumen of the gut will reduce the efficiency of chylomicron formation, which will result in greater portal uptake of dietary fatty acids bound to albumin (12). The liver will thus be stimulated by insulin to synthesize lipid de novo from carbohydrate and will also be directly exposed to a greater proportion of dietary fatty acid for lipid synthesis. A low-GI diet early on in the disease process may help to break this vicious cycle.
Some evidence exists that low-GI diets are beneficial to persons with type 2 diabetes (13). Similarly, cohort studies suggest that the risks of type 2 diabetes and coronary heart disease may be reduced by low-GI diets, and preliminary studies have shown better body weight control in children following low-GI diets. The current article by Valtueña et al suggests that persons with NAFL could also benefit from this approach.
Low-GI diets have also been associated with lower serum concentrations of triacylglycerol (14) and C-reactive protein (15, 16). C-reactive protein and other acute-phase proteins are synthesized by the liver in response to proinflammatory cytokines that are generated in adipose tissue. Reductions in hepatic triacylglycerols and acute-phase protein synthesis may also be factors in preventing both the progression of NAFL to NASH and more serious clinical sequelae. Future studies must now assess whether a low-GI diet, given as an intervention, makes a difference in the natural history of NAFL.
ACKNOWLEDGMENTS
DJAJ has served on the Scientific Advisory Boards of Unilever and Solae and has received research funding from Unilever, The Solae Company, the Almond Board of California, and Barilla America Inc and Loblaw Companies Ltd. DJAJ and CWCK have been on the speakers' panel for the Almond Board of California. None of the other authors had any conflict of interest.
REFERENCES
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