Reply to: “Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients”
Authors: Salvatore Petta, Giulio Marchesini, Antonio Craxì
Journal: Journal of Hepatology (2013)

Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patientsJournal of HepatologyVol. 60Issue 3PreviewTo the Editor: Full-Text PDF Open AccessIndustrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patientsJournal of HepatologyVol. 59Issue 6PreviewUnhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology. Full-Text PDF To the Editor: Prof. Kitson’s comments give us the opportunity to clarify some issues that were not completely dealt with in our manuscript. In the study we reported a link between fructose intake and the severity of liver fibrosis in a cohort of Italian patients with genotype 1 chronic hepatitis C (CHC) [[1]Petta S. Marchesini G. Caracausi L. Macaluso F.S. Cammà C. Ciminnisi S. et al.Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients.J Hepatol. 2013; 59: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], with an association found for industrial, but not for fruit fructose intake. Our results were in keeping with data already reported in patients with non-alcoholic fatty liver disease [2Abdelmalek M.F. Suzuki A. Guy C. Unalp-Arida A. Colvin R. Johnson R.J. et al.Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1961-1971Crossref PubMed Scopus (512) Google Scholar, 3Sanyal A.J. Chalasani N. Kowdley K.V. McCullough A. Diehl A.M. Bass N.M. et al.NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.N Engl J Med. 2010; 362: 1675-1685Crossref PubMed Scopus (2193) Google Scholar]. Prof. Kitson and his colleagues question firstly the appropriateness of using a web-based calculator of U.S. origin (www.healthdiet.us/fructose) to assess fructose intake in the Italian population, due to a presumed much lower fructose consumption in the latter. Actually, we considered industrial fructose as any amount of fructose derived from food sources containing high fructose corn syrup (beverages like soft drink and fruit juices, processed foods like fast-food, especially when enriched with industrial sauces). The U.S. database for the calculation of fructose intake is most likely valid also for use in Italian patients, since the majority of foods and beverages with added fructose are produced by multinational companies, and the concentration of fructose does not change among countries. In addition, our data on fructose consumption are in keeping with another Italian report [[4]Leclercq C. Arcella D. Piccinelli R. Sette S. Le Donne C. Turrini A. The Italian national food consumption survey INRAN.SCAI 2005–06: main results in terms of food consumption.Public Health Nutr. 2009; 12: 2504-2532Crossref PubMed Scopus (313) Google Scholar]. Prof. Kitson and colleagues also question the validity of a three-day food diary. It has been reported that a three-day diary record correlates closely with a longer 9-day diary [[5]Yang Y.J. Kim M.K. Hwang S.H. Ahn Y. Shim J.E. Kim D.H. Relative validities of 3-day food records and the food frequency questionnaire.Nutr Res Pract. 2010; 4: 142-148Crossref PubMed Google Scholar], providing a solid dietary assessment. In a cross-sectional analysis no inference can be made regarding a possible causal relationship, but this possibility may be postulated. We have simply described the positive association between industrial fructose and advanced fibrosis, but the two conditions might also share common pathogenic mechanisms. As a second point, our study was performed in an Italian population, not in an Australian or U.S. population, where much higher rates of fructose consumption are recorded. The accuracy of our computation of fructose intake is in keeping with the industrial fructose intake reported in the Italian population [[4]Leclercq C. Arcella D. Piccinelli R. Sette S. Le Donne C. Turrini A. The Italian national food consumption survey INRAN.SCAI 2005–06: main results in terms of food consumption.Public Health Nutr. 2009; 12: 2504-2532Crossref PubMed Scopus (313) Google Scholar], but lower than in the U.S. population. In the participants of the LOOK Ahead study consuming ⩾15 g/day of fructose (high-fructose consumers), a fructose challenge identified metabolic abnormalities potentially responsible for NAFLD progression [[6]Abdelmalek M.F. Lazo M. Horska A. Bonekamp S. Lipkin E.W. Balasubramanyam A. Fatty Liver Subgroup of Look AHEAD Research Group. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes.Hepatology. 2012; 56: 952-960Crossref PubMed Scopus (136) Google Scholar]. This threshold was observed in most of our cases with fibrosis, and the higher industrial fructose intake was the major source of difference between cases with advanced vs. mild hepatic fibrosis. When industrial fructose intake as continuous variable was replaced in the model by industrial fructose as categorical variable, 14/25 patients consuming ⩾8 g/day industrial fructose had F3-F4 fibrosis vs. 18/89 in the group with lower intake (p = 0.01). Thirdly, Kitson et al. remark the lack of association between severe liver fibrosis and both insulin resistance (IR) and steatosis in this specific population. In the present series, steatosis was linked to fibrosis at both univariate and multivariate analysis. Both IR and steatosis, the phenotypic hepatic expression of IR, are risk factors for fibrosis; they both might play an important role in fibrosis progression and are likely to be variably combined in different settings [7Petta S. Cammà C. Di Marco V. Alessi N. Cabibi D. Caldarella R. et al.Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection.Am J Gastroenterol. 2008; 103: 1136-1144Crossref PubMed Scopus (161) Google Scholar, 8Petta S. Amato M. Cabibi D. Cammà C. Di Marco V. Giordano C. et al.Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1.Hepatology. 2010; 52: 1543-1552Crossref PubMed Scopus (86) Google Scholar]. As to the possible reason(s) why industrial, not fruit fructose intake, is associated with the severity of liver fibrosis in CHC, several tentative hypotheses may be suggested. In fresh fruit the deleterious effects of fructose might be counterbalanced by the positive effects of other nutrients (e.g., fibers) and antioxidants, not present in industrial fructose. In processed food, the glucose of high-fructose corn syrup might accelerate fructose absorption, making industrial sugars unhealthy. Finally, even if the link between industrial fructose and the clinico-pathological features (i.e., liver fibrosis and obesity) was independent of energy intake on a statistical basis, we cannot rule out a pivotal role of calories and/or of a less healthy diet and lifestyle in the reported association, considering that higher amounts of industrial fructose were associated with high-calorie diets. Hence we are confident that our study provides reliable evidence, albeit of an associative nature. Further research is clearly needed to provide external validation and to eventually elucidate the pathophysiological basis, aiming to a healthy diet as an additional tool to manage patients with HCV-induced chronic liver disease. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.