The present study compared dietary constituents, physical activity and liver ultrasound in patients with fatty liver. We found that NAFLD patients without classic risk factors consume more soft drinks and juices than healthy controls. The follow-up data, the correlation between severity of fatty liver and amount of soft drink consumption, and the fact that soft drink consumption was the only independent predictor of fatty liver support the association between soft drink consumption and fatty liver. As expected, insulin resistance (HOMA-IRI) and MDA levels were higher in the group with fatty liver. However, when controlled for other factors, soft drink beverage consumption was the only independent variable that correctly predicted the presence of fatty liver.
The underlying mechanism for this association remains unknown. Soft drink consumption is the leading cause of added sugar in the diet (1 tsp of sugar contains 4.2 g) (17
). Individuals who consume an excessive amount of soft drinks tend to lead a sedentary lifestyle and eat a higher calorie diet (an additional 150 kcal/day to 300 kcal/day) that includes more fructose (18
). Because both regular Coca-Cola and Diet Coke consumption in our study resulted in an increased risk of fatty liver, factors other than calories and sugar content likely contribute to the higher risk. These factors include the consumption of fructose, aspartame, caramel (food colourant) and other covariants. These complexes of sugars and colourants may promote insulin resistance, lipid peroxidation and hepatic inflammation, and are a source of glycation end products (5
). The extent to which excessive fructose, aspartame and caramel consumption might contribute to the high prevalence of liver disease in western societies and to the progression of NAFLD to NASH has not been investigated. One study of lean women found that four days of overfeeding with sucrose (glucose plus fructose) drink increased de novo lipogenesis by 200% to 300% (21
). Another feeding study showed that two days of a high-fructose diet (30% of the total energy consumed per day, consumed as a sweetened beverage at every meal) resulted in decreased postprandial glucose concentration and insulin response, and prolonged alimentary lipemia in women (22
). Another follow-up study indicated that both surplus calories and excessive sucrose consumption play a role in the rise of liver enzyme levels (23
). Additional evidence that fructose can cause steatohepatitis is that intravenous administration of fructose to healthy volunteers has resulted in a 75% decrease in hepatic ATP within 10 min because the liver was overwhelmed and could not metabolize it (24
). Fructose can also increase triglyceride levels, de novo synthesis of fatty acids, hyperuricemia and insulin resistance (25
). The triglyceride response to fructose ingestion appears to depend on whether a person is carbohydrate-sensitive or insulin-resistant (26
). Fructose, especially high-fructose corn syrup, is now used extensively in carbonated beverages and other sweetened drinks, baked goods, candies, canned fruits, sodas, jams, jellies and dairy products (27
After absorption in the small bowel, fructose is transported via the portal vein to the liver, where it is metabolized by fructokinase to fructose-1-phosphate. This molecule is cleaved by aldolase to form glycerone phosphate and glyceraldehyde-3-phosphate, both of which can be further metabolized in the glycolytic pathway (28
). An increase in serum triglycerides and, ultimately, increased low-density lipoprotein cholesterol concentration may result from enhanced fatty acid synthesis, increased esterification of fatty acids and increased very low-density lipoprotein secretion (28
). A soft drink containing 32.6 g of fructose could increase the fasting serum fructose fourfold. A 340 g soft drink sweetened with fructose-55 contains approximately 40 g of the sweetener (ie, 22 g of fructose and 17 g of glucose, representing a fructose excess of 5 g per can) (20
). Fructose affects each of the three major factors that are believed to contribute to the pathogenesis of diabetic end organ damage. These factors are glycosylation of tissue proteins, intracellular accumulation of sorbitol and oxidative stress (4
). The association between the consumption of beverages sweetened with sugars such as HFCS and the risk of diabetes has been established by Schultze et al (20
From our study, it seems that fructose is not the only risk factor of liver disease, because 40% of our cohort were drinking Diet Coke sweetened with aspartame. Aspartame is absorbed from the intestine and metabolized by the liver to form phenylalanine, aspartic acid and methanol. This process causes mitochondrial dysfunction and ATP depletion, which contribute to accumulation of fat (29
). Also, regarding obesity and aspartame, formaldehyde converted from the free methyl alcohol accumulates in the cells and damages mitochondrial DNA, with most toxicity effects occurring in the liver. Finally, the effect of caramel colourant has been incriminated as a cause of elevated liver enzymes and may be a potential source of advanced glycation end product, which may promote insulin resistance and can be proinflammatory (5
). The extent to which fructose, aspartame and caramel contributed to severe fatty liver could not be concluded due to the small size of the cohort.
When controlled for other factors, including dietary composition and physical activity, soft drink beverage consumption was the only independent variable that could correctly classify the presence of fatty infiltration of the liver. A study by Vartanian et al (30
) showed a clear association among soft drink intake, diabetes and the metabolic syndrome, confirming our finding. Although we still do not know the most common soft drink that induces fatty liver, fructose, caramel and aspartame constituents may have a role. These coingestants might also increase the risk for fatty liver because of their high amount of rapidly absorbable carbohydrates (20
). They contain a large amount of HFCS, which has a similar effect on blood glucose as sucrose (31
). The consumption of sugar-sweetened soft drinks therefore induces a fast and dramatic increase in both glucose and insulin concentration (32
). In addition, cola-type soft drink caramel colouring is rich in advanced glycation end products, which may increase insulin resistance and inflammation (6
). The US Food and Drug Administration has established 51 mg of aspartame and 200 mg of caramel colouring per kg body weight as an acceptable daily intake. The natural history of NAFLD is not known. The present study may add important insight into the role of sugar-sweetened beverage consumption as a cause of fatty liver in those without risk factors. The time from NAFLD diagnosis to enrolment in the study was less than two weeks. Therefore, the information obtained for dietary food consumption was a good reflection of the patient’s dietary habits before the diagnosis of NAFLD.
Some limitations merit further comment. The first limitation is the use of ultrasound to assess liver fat content. However, the sensitivity (92%) and specificity (100%) of ultrasound to show increased fatty infiltration are very good, and its accuracy approaches 100% for patients with moderate to severe steatosis (34
). The second limitation is that other covariants present in the food or some dietary habits (eg, drinking carbonated beverages facilitates the intake of fatty food such as pizza) may have played a role in the observed relationship between soft drink beverages and hepatic steatosis. Third, the number of patients and controls was small for a study relating to dietary habits in which variability and errors are possible. A much larger patient group with a stronger power to look for unmeasured confounding variables or bias by control selection is needed. Finally, dietary and physical activity information was obtained through self-reported questionnaires, which may be subject to under-reporting and interviewer bias. However, these questionnaires were validated and were appropriate in capturing their usual dietary intake. In addition, the dietary collection was for two seven-day records (at the beginning and the end of the study period), yet the results were extrapolated over 36 months. This has been validated by Pisani et al (35
). The rationale behind this is compliance, ethnic background and the sociocultural homogeneity of the population studied. Traditional habits in cooking practices are quite similar throughout the region and tend to persist in their descendents. The findings of the present study should not be directly extrapolated to ‘general NAFLD patients’ because we compared soft drink consumption in an atypical group of NAFLD patients (ie, no classic risk factors, 10% of the general population).