The potential role for iron overload and fungal infection in liver transplantation

The study published by Alexander et al. in this issue of Liver Transplantation raises a very interesting and provocative hypothesis that the presence of stainable iron in the hepatic explant of patients undergoing liver transplantation was found to be associated with invasive fungal infection. This association could be demonstrated in both univariate andmultivariate modeling. The univariate model was consistent with many of the already published risk factors for invasive fungal infection. However, the authors readily admit that they did not have access to all the risk factors that have been demonstrated to be associated with invasive fungal infection, such as volume of blood transfused, antibiotic use, development of bacteremia, or colonization with fungal species such as candida. In addition, the authors did not have measures of iron, or transferrin, which might have further elucidated the pathogenesis of invasive fungal infections in these patients. It should also be pointed out that in this group of patients, systemic antifungal prophylaxis was not employed. Despite these limitations, I believe the report is extremely valuable and may point out another risk factor that should be considered from both a surveillance and prevention standpoint, namely iron overload. As the authors note, this association has been demonstrated in bone marrow transplantation. To my knowledge this is the first report in liver transplantation, although iron overload and the use of iron chelating agents have long been recognized as risk factors for mucormycosis. Although the role of iron in the pathogenesis of infections has been well documented, the exact role in the clinical setting remains controversial. Iron is an essential component for bacterial virulence in many settings, including animal models of pyelonephritis and enteric infections caused by Yersinia enterocolitica. It has also been shown that iron overload may facilitate enhanced viral replication in hepatitis B. Conversely, lactoferrin, an iron binding protein present in several body secretions and polymorphonuclear leukocytes granules, has been shown to inhibit herpes simplex, human immunodeficiency virus, and cytomegalovirus infection. Lactoferrin may become saturated in iron overload states, and the inhibitory effects may become reversed. Presumably this is one of the mechanisms in which iron overload could predispose patients to infection. Iron does play a role in the function of phagocytes, as well as T and B cells. Therefore, it could be postulated that iron excess could inhibit phagocytic function, as well as specific T and B cell function, thus leading to an increased risk for fungal infection. Experimental models of infection have confirmed such physiologic derangements, although data in humans is scarce. We, and others, have demonstrated such an effect in hemodialysis patients. The authors have brought a very important potential association to the liver transplant community and are to be commended for this hypothesis-generating paper, which will, hopefully, be followed with a prospective study that includes iron markers in serum or plasma, as well as observational studies of other risk factors known to be associated with invasive fungal infection.