Increased levels of iron can contribute to increased generation of ROS and other radical or non-radical intermediates, resulting in a potentiation of cytotoxic, pro-inflammatory or pro-fibrogenic consequences. The role of iron in CLD progression. Hereditary hemochromatosis (HH) is a long-lasting disease in which hepatic iron levels increase progressively over a long period during which no or relatively modest inflammation and injury can be detected; when hepatic levels of iron increase to over 60 mmol/g dry weight, HSCs become activated and fibrogenesis becomes significant , although this transition (from non-fibrotic to fibrotic and then later cirrhotic) is not yet completely clear and other risk factors (ethanol consumption and ALD, chronic infection by HCV, concomitant metabolic conditions leading to NAFLD) are likely to be involved. However, with regard to patients with chronic HCV infection, it has been proposed that mutations in the hereditary hemochromatosis HFE gene may be responsible not only for derangement of iron homeostasis and HH, but may also worsen or accelerate the course of CLD by eliciting a turn-over of redox active iron in both the liver and plasma; in other words, the hypothesis is that HFE mutations may additionally result in increased intracellular production of ROS and free radicals taking place in hepatocytes or, also on the basis of recent knowledge on the role of hepcidin (see the section 'ROS-dependent sustained activation of JNK: a common step in oxidative stress-dependent cell death') and the iron transporter ferroportin, may affect the ability of Kupffer cells to handle and retain iron [112, 114, 115]. Chronic HCV infection. In addition to what has been reported for HH, it should be recalled that non-hereditary (that is, secondary) increased hepatic iron levels have been shown to represent a significant determinant for both the severity and progression rate of CLD associated with chronic HCV infection. Along these lines, different laboratories have shown a correlation between liver iron levels and HSC activation as well as fibrosis progression [114, 115], which can be significantly prevented by phlebotomy. It should be noted (reviewed in ), however, that other researchers did not find evidence for such a correlation. NAFLD and NASH. With regard to NAFLD, current evidence suggests that metabolic disturbances leading to steatosis (as associated with obese or overweight patients and, usually, with the so-called metabolic syndrome, often also including diabetes and insulin resistance) are likely to represent the 'first hit'. In order for NAFLD to progress to non-alcoholic steatohepatitis or NASH a 'second hit' (see later) is believed to be necessary and usually identified as occurrence of oxidative stress. Along these lines, iron is a rather obvious candidate because of its well known role as an ideal metal catalyst for the generation of ROS and other free-radical or non-radical intermediates. Alcoholic liver disease (ALD). Homologous considerations (that is, the role of hepatic iron levels) may be advanced for ALD and may help to explain, at least in part, why only approximately 30% of patients with high levels of chronic alcohol consumption are likely to develop cirrhosis over time. As recently reviewed , there are several reasons to believe that iron is a serious and, likely, independent candidate factor able to contribute to progression of ALD to cirrhosis. For example, in the pre-cirrhotic stage, approximately 30% of ALD patients show an elevated hepatic iron index, but when the ALD progresses to cirrhosis the percentage of ALD patients having iron overload rises up to 60%. Interestingly, it was recently suggested that ethanol consumption is able to alter IL-6-dependent expression of hepcidin, a condition resulting in enhanced absorption of iron and hepatic siderosis . Other mechanisms that may enhance iron hepatic levels have been recently reviewed by Brittenham .