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Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients

Open AccessPublished:October 28, 2013DOI:https://doi.org/10.1016/j.jhep.2013.10.013

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      To the Editor:
      In their study recently published in the Journal of Hepatology, Petta et al. reported an independent association between advanced liver fibrosis in chronic hepatitis C virus (HCV) genotype 1 infection and ‘industrial’, but not fruit fructose intake [
      • Petta S.
      • Marchesini G.
      • Caracausi L.
      • Macalauso F.S.
      • Camma 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.
      ]. While these findings are novel we believe this cross-sectional study has significant limitations that need to be addressed before the results can be applied to the broader HCV community.
      Firstly, the use of an American web-based calculator (www.health-diet.us/fructose) to quantify the fructose content of specific foods requires validation in an Italian population consuming locally produced and marketed food. The United States uses high fructose corn syrup as an additive sweetener to food and carbonated beverages to a much higher extent than many other countries. Hence the methodology used to calculate ‘industrial’ fructose intake may have resulted in significant bias being introduced into the study. The authors have not given any specific information of the use of high fructose corn syrup as a sweetener in Italy, but solely relied on extrapolation from American data and practices. Furthermore, the methodology of use of a three-day food diary is questionable when the progression of fibrosis in HCV infection occurs over years.
      Secondly, the very low overall fructose intake by study participants (18.0 ± 8.7 g/day) limits the generalizability of the study. This low value is likely reflective of the regional dietary differences many Italians have when compared with other developed countries, including the United States of America. National dietary intake survey data shows that >95% of American residents consume <100 g of fructose per day from all sources [
      • Livesey G.
      Fructose ingestion: dose-dependent responses in health research.
      ], while Australian adults consume <60 g total fructose per day [

      Australian Bureau of Statistics, National Nutrition Survey 1995: nutrient intakes and physical measurements.

      ]. These values are markedly higher than this study’s population. Moreover, as those with advanced fibrosis only had 2.3 g higher mean intake of ‘industrial’ fructose per day than those without advanced fibrosis and the clinical relevance of such a small increase in this form of fructose is questionable.
      Thirdly, this study did not find any relationship between insulin resistance and advanced fibrosis. Insulin resistance is a marker of glycaemic control and has been identified by a number of investigators, including Petta’s group, to be an important cofactor in the development of advanced liver fibrosis in genotype 1 infection [
      • Hui J.M.
      • Sud A.
      • Farrell G.C.
      • Bandara P.
      • Byth K.
      • Kench J.G.
      • et al.
      Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected].
      ,
      • Muzzi A.
      • Leandro G.
      • Rubbia-Brandt L.
      • James R.
      • Keiser O.
      • Malinverni R.
      • et al.
      Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients.
      ,
      • Petta S.
      • Camma 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.
      ,
      • Moucari R.
      • Asselah T.
      • Cazals-Hatem D.
      • Voitot H.
      • Boyer N.
      • Ripault N.P.
      • et al.
      Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis.
      ]. The lack of an association between insulin resistance and advanced fibrosis, as well as steatosis, in both univariate and multivariate analysis in this study cohort raises concern about the internal validity of the study’s findings. Of particular note diabetes, insulin resistance, HOMA score, blood glucose levels, insulin levels, body mass index, and other anthropometric measures were not included in the same multivariate analysis. The authors state that this method was employed to ‘avoid colinearity’, but their statistical methodology may explain why no association between insulin resistance and fibrosis was seen.
      Most importantly however, is the lack of a plausible explanation given by the authors as to why the specific source of fructose, whether from ‘natural’ apples or ‘industrial’ cola, would have an impact on liver fibrosis rather than the degree of consumption of the monosaccharide itself. Indeed, fructose is the same compound regardless of the source, with ‘industrial’ derived fructose unlikely to have a differential unfavorable impact on caloric intake and metabolic profile. A more credible explanation is that those who have higher ‘industrial’ fructose intake are likely to have a less healthy diet and lifestyle, resulting in higher rates of obesity and insulin resistance. Our suggestion is that the key findings of this study are likely to represent a confounding relationship, brought about by gaping methodologic flaws. Our viewpoint is further supported by the independent association between ‘industrial’ fructose intake and obesity that the study describes.

      Financial support

      Dr. Matthew T Kitson has received funding from the National Health and Medical Research Council of Australia.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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