The measurement of SF in RAD001 normal patients and patients with hereditary hemochromatosis is a reliable reflection of body iron stores and hepatic iron concentration.5 However, SF is often increased in liver disease per se, probably because of release of ferritin molecules and reduced clearance of ferritin from the circulation. Thus, in many patients with liver disease, SF simply reflects hepatic necroinflammatory activity rather than increased body iron stores. Serum ferritin concentration is also frequently increased in infection, systemic inflammatory conditions, and malignancy.5-7 The exact pathophysiological

mechanism in end-stage liver disease that explains the relationship between SF and OLT waiting list mortality is uncertain. It is important to consider whether this relationship is attributable to increased liver iron stores promoting further hepatocyte injury. Approximately 30% of patients with advanced cirrhosis attributable to hepatocellular forms of liver disease have increased hepatic iron concentration independent of the HFE mutations. Serum ferritin concentration is usually increased in these subjects.16, Smad inhibitor 17 Although controversial, some studies suggest that these patients have increased pretransplantation and posttransplantation mortality as well as an increased risk of HCC.18,

19 Difficulty in obtaining liver tissue for the measurement of hepatic iron concentration has precluded large prospective studies addressing the effect of increased liver iron on the natural history of end-stage liver disease. However, magnetic resonance imaging technology to accurately measure hepatic iron concentration

(FerriScan) using noninvasive techniques provides a method for studying patients with cirrhosis.20 Increased hepatic necroinflammatory activity accompanied by worsening liver function is a possible explanation of the relationship MCE between SF and waiting list mortality. This possibility is supported by the positive correlation between serum alanine transaminase levels and SF in this cohort. However, the correlation coefficient describing this relationship suggests that important factors in addition to serum alanine transferase concentration (and necroinflammation) also contribute to the elevated SF in advanced liver disease. Recently, Ruddell et al.21 proposed that ferritin functions as a proinflammatory cytokine, and this may have relevance to the findings of this study. Subjects with active or recent infection (within the previous month) were excluded from the Australian study cohort. Therefore, the relationship between mortality and SF is unlikely to be explained by an intercurrent infection. Similarly, the effect of SF on mortality was independent of the presence of HCC and other malignancies.