
In the February 2006 issue of Bone Marrow Transplantation, Rizzo et al. 1 outline the recommendations for screening and preventive practices for long-term survivors. As described, iron overload in long-term transplant survivors has not been studied extensively. Consensus is lacking regarding the definition, incidence, clinical significance, diagnostic criteria and therapy for this disorder. In adults, transfusion-associated iron overload generally occurs after infusion of 100-150 U of packed red cells (PRBCs) (the equivalent of 25-40 g of elemental iron). 2 However, in autologus and allogeneic hematopoietic transplant recipients, iron overload has been reported with infusion of less than 50-60 U of PRBCs. [3] [4] [5] [6] Increased intestinal iron absorption in these is likely related to aberrant hepcidin regulation, although in the past, chemotherapy or graft-versus-host disease (GVHD) related intestinal epithelial injury was implicated. 6, 7 Apart from its harmful effects on organ function (liver, heart, endocrine organs), iron overload can also result in worsening of viral hepatitis and its response to therapy, worsening of hepatic GVHD, and increased risk of opportunistic infections (Yersinia enterocolitica, Vibrio vulnificans, Listeria monocytogenes, Aspergillosis and Mucormycoses). 4, 6, [8] [9] [10] Hyperferritinemia is a common late effect of hematopoietic transplantation. 3 Although serum ferritin level does not correctly reflect body iron stores in all clinical circumstances, the combination of elevated ferritin with elevated transferrin saturation accurately identifies patients with increased body iron stores. 8 At 1 year post transplant, when inflammatory stress has largely subsided, most patients have a serum ferritin of o1000 mg/dL and no clinical evidence of iron-overload; serum ferritin in these patients declines slowly with time. 9 In another group of patients, however, issues such as viral hepatitis (25-50% incidence in some series) and GVHD affect both liver function tests and serum ferritin, 3, 4 and confound the diagnosis of clinically significant iron overload. Jensen et al., 9 identified liver iron concentrations of 300-350 mM/g as a critical level above which hepatocelluar injury, as reflected by aminotransferase elevation, was likely to occur. Both increased urinary iron excretion (415 mg/24 h) and serum ferritin 41000 mg/dL (R 2 ¼ 0.55, Po0.0001) correlated with alanine aminotransferase elevation and high liver iron. Therefore, in the absence of data from liver biopsy, it appears that clinically significant iron overload does not occur until serum ferritin levels are greater than 1000 mg/dL. Few studies report the clinical significance of iron overload in transplant survivors. However, Butt et al. 5 reported on serum iron parameters in 32 long-term survivors of acute myelogenous leukemia (allogeneic ¼ 6, autologus ¼ 10, chemotherapy ¼ 16). These patients had a median serum ferritin of 1223 mg/dL at a median of 1321 days after last transfusion, confirming the presence of significant iron overload years later. In the only study describing hyperferritinemia in a group of transplant survivors, 88% of 76 patients (40 autologous and 36 allogeneic) had elevated serum ferritin and 50% of these values were 41000 mg/dL. Unfortunately, data on the clinical manifestations of iron overload is lacking in these reports.

As ferritin elevation is frequent, defining the clinical manifestations attributable to iron overload is critical. Two studies characterize liver disease following hematopoietic transplants. In a study of 106 allogeneic transplant recipients, 57% developed chronic liver disease. 4 In 47% of these cases, more than one etiologic factor coexisted including iron overload (52%), hepatitis C infection (47%), GVHD (37%), hepatitis B infection (7%), nonalcoholic steatohepatitis (5%), and autoimmune hepatitis (5%). Similar rates of liver disease and coexisting factors were identified in another study of 121 allogeneic and autologous transplant patients. 10 Thus establishing a diagnosis of iron overload should involve exclusion of viral hepatitis, and if feasible, quantification of hepatic parenchymal iron with magnetic susceptibility using a super conduction quantum interference device (SQUID), magnetic resonance study, or a liver biopsy. This is particularly important in cases where more than one process may be present. 4 HFE studies may be warranted to exclude genetic predisposition for iron overload using DNA samples representative of the patient (buccal swab or prestored DNA sample) and not the donor (hematopoietic tissues).

In hematopoietic transplant recipients with an established diagnosis of GVHD, worsening liver function tests are often interpreted as an exacerbation of liver GVHD resulting in empiric intensification of immunosuppressive therapy. 6 Recognition that iron overload may complicate the picture provides crucial therapeutic direction. We and others have demonstrated that phlebotomy with or without erythropoietin assistance is well tolerated and effects iron depletion in a predictable and rapid manner. 5, 6 Erythropoietin support allows uninterrupted phlebotomy by preventing iatrogenic anemia and by mobilizing stored iron. With aggressive phlebotomy, the average time to successful normalization of transaminases and serum ferritin is 7 months and 11 months, respectively. 6 Maintenance phlebotomy is required every 3-6 months to prevent iron reaccumulation and to keep serum ferritin in a low normal range. 6, 8 Iron overload after transfusion of only 50-60 U of PRBCs in transplant recipients combined with the gradual rise in ferritin after successful iron depletion suggests that there is a signal for increased iron absorption, and that the signal persists well beyond the peritransplant period. Based on what is now known about iron homeostasis, one would expect hepcidin levels to be low permitting increased intestinal iron absorption and increased iron release from storage sites such as the hepatocyte and the macrophage. As a result, serum iron levels should be elevated. Hepcidin levels generally rise and hinder iron absorption during inflammatory state. Thus it may be that post-transplant immunosuppressants reduce the level of cytokines that normally stimulate hepcidin production and allow increased absorption of dietary iron. In addition, hepatic GVHD may result in disordered hepcidin regulation, 7 as it likely does in chronic viral hepatitis, and might explain increased risk of iron overload and need for maintenance phlebotomy after successful iron depletion.

Prospective well-designed studies are needed to define the prevalence of clinically significant iron overload and to establish guidelines for screening in survivors of hematologic malignancy. Such studies will define the value of routine screening with serum ferritin, evaluate hepatic iron load with noninvasive magnetic resonance imaging and identify a subgroup of patients who might benefit from phlebotomy or oral iron chelating agents. The hypothesis that hepcidin levels are low in these patients can also be tested and a correlation with serum cytokine levels can be made. Until guidelines are available, we recommend measurement of serum ferritin in all patients with unexplained abnormal liver functions, and routine screening 6-12 months post-transplant even in asymptomatic patients. 

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