Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver
Authors: Paola Loria, Amedeo Lonardo, Nicola Carulli
Journal: Hepatology (2004)

We read with interest the paper by Bugianesi et al. recently published in HEPATOLOGY where fibrosis in nonalcoholic fatty liver disease (NAFLD) was thought to be associated with insulin resistance but not iron overload.1 We would like to provide some preliminary data from the Polistena project that reached similar results. The Polistena project, which started in 1998 in Modena, Italy, is a study specifically aimed at NAFLD in which 161 consecutive NAFLD cases have been enrolled so far. This series is unique because patients were referred by participating general practitioners on the basis of ultrasonographic evidence of "bright liver" and not on the basis of obesity, diabetes, hyperlipidemia, symptoms/signs of liver disease or altered liver function tests, or biochemical parameters of iron overload.2, 3 Sixty-one biopsied NAFLD patients from the Polistena series were classified as types 1 to 4 according to Matteoni et al.4 The following parameters were studied: age, body mass index, waist circumference, cholesterol, triglycerides, uric acid, alanine aminotransferase, ferritin, transferrin percent saturation, hemochromatosis gene (HFE) gene mutations, and indexes of insulin resistance. Median values (25th 75th percentile) of parameters significantly different (grades 1 and 2 vs. grades 3 and 4, P < .05) are shown in Table 1. This suggests that insulin resistance is closely associated to histologically advanced NAFLD in our series and probably has a key role in the pathogenesis of the fibrotic evolution of this disease. In our overall series (HFE gene mutations data available in 122/161 cases), the prevalence of heterozygous C282Y and H63D HFE gene mutations is in the same order of magnitude as in the healthy Italian population.5 Information about HFE gene mutations was available in 52 out of the 61 biopsied patients. Table 2 summarizes the distribution of early and advanced NAFLD cases according to HFE gene status. Although the majority of heterozygous patients tend to fall within the "advanced" NAFLD category while the majority of homozygous patients show an "early" NAFLD, this trend does not reach statistical significance (P = .07). Furthermore, HFE heterozygosity does not associate with any significant effect on biochemical phenotype and insulin resistance assessed through Homeostasis Model Assessment Insulin Resistance (data not shown). In conclusion, data from the Polistena study support the hypothesis that insulin resistance appears not only to trigger the development of NAFLD but also to worsen the course of this disease. Such findings, along with the Bugianesi study, fully support the concept that one hit (namely, insulin resistance) is enough to account for a large part of the spectrum of primary NAFLD. The clinical implication of these findings is that insulin resistance (and not iron depletion per se) represents the primary therapeutic aim in NAFLD.2 Interestingly, this lesson might also be applied to those cases where NAFLD exists with other hepatotoxic factors, such as chronic hepatitis C virus infection.6 Whether insulin resistance in primary NAFLD is a peripheral (merely metabolic) or a central (endocrine due to growth hormone deficiency) phenomenon7 remains a fascinating but as yet unsettled issue. Paola Loria*, Amedeo Lonardo , Nicola Carulli*, * Università degli Studi di Modena e Reggio Emilia, Italy, Ospedale Civile - Unità Operativa Medicina e Gastroenterologia Modena, Italy.