Iron chelation beyond transfusion iron overload
Antonello PietrangeloCenter for Hemochromatosis, University Hospital of Modena and Reggio Emilia, Modena, Italy
The effects of systemic iron overload in hereditary (e.g., classic HFE hemochromatosis) or acquired disor-ders (e.g., transfusion-dependent iron overload) are well known. Several other iron overload diseases, withan observed mild-to-moderate increase in iron in selected organs (e.g., the liver or the brain), or with ‘‘mis-distribution’’ of iron within cells (e.g., reticuloendothelial cells) or subcellular organelles (e.g., mitochon-dria), have been recognized more recently. The deleterious impact of any excess iron may be high as activeredox iron may directly contribute to cell damage or affect signaling pathways involved in cell necrosis–apoptosis or organ fibrosis and cancer. This article discusses the potential use of iron chelation therapyto treat iron overload from causes other than transfusion overload. Am. J. Hematol. 82:1142–1146,2007. VVC 2007 Wiley-Liss, Inc.
IntroductionIron overload is involved in the pathogenesis of many
human diseases. Iron accumulation essentially results fromeither increased cell iron influx or decreased efflux, or, aswe are just now beginning to recognize, altered subcellulariron traffic (Fig. 1) [1]. When considering iron distribution,specific pathologic states in humans result from systemiciron overload (e.g., hemochromatosis, posttransfusion sid-erosis, etc.). Other disorders are associated instead with‘‘regional’’ accumulation of iron in subcellular compartments(e.g., mitochondria in Friedreich’s ataxia) or with certain celltypes (e.g., macrophages in anemia of chronic disease andclassic ferroportin disease) or organs (the liver in viral hep-atitis or the brain in some neurodegenerative disorders) [1].In strict terms, the latter disorders may not all qualify astrue iron overload states, as total body iron content maynot be increased. Nevertheless, the impact on cell damageand organ disease may be extremely high even in the pres-ence of mild iron overload, as any excess iron may fuel oxi-dative stress and affect signaling pathways important forthe pathogenesis of that specific condition.This knowledge has led us to reconsider the traditional
approach to iron removal strategies, and has broadened theindication for the use of phlebotomy and, particularly, ironchelation. This article provides examples of diseases whereiron chelation therapy may prove useful in the near future.
Systemic Iron Overload: HemochromatosisAmong all iron loading disorders, hereditary hemochro-
matosis and transfusion-dependent iron overload in heredi-tary anemias, particularly thalassemia, are central whenconsidering epidemiological impact, extent of iron burden,and risk for iron-related morbidity and mortality. The thera-peutic approach to these diseases has been based on a‘dichotomy’: phlebotomy is indicated for hemochromatosispatients, and iron chelation is the gold standard for treatingtransfusion iron overload in hereditary anemias. However,in practice, there are clear limitations to this rigid scheme.For example, while the therapeutic management for hemo-chromatosis involves phlebotomy (venesection), specificchelators are emerging based on the improved pathophys-iological understanding of iron overload diseases. Phlebot-omy in hemochromatosis has some limitations: patientsmay be intolerant, or have a low acceptance of it; it may bedifficult to gain peripheral vein access; and it is contraindi-cated in patients with severe heart disease or anemia.
However, the literature on the use of chelators in classichemochromatosis is limited to case reports, mainly basedon the use of deferoxamine [2–5]. A recent study by Fabioet al. demonstrated that combined chelation therapy withdeferoxamine and deferiprone successfully reversed theeffects of heart failure in the setting of unrecognized juve-nile hemochromatosis [6]. Therefore, iron chelation mayprove useful in hemochromatosis cases where phlebotomyis not indicated or feasible.
Regional Iron Accumulation: Viral HepatitisAnd Fatty Liver DiseaseBeyond primary iron overload states associated with
massive iron excess, an increasing number of other ironoverload conditions have been recognized in which anobserved mild or moderate increase of iron stores appearsto have significant clinical relevance. This is the case ofchronic hepatitis C, insulin resistance-associated hepaticiron overload syndrome, and end-stage liver disease [7–12](see below). In fact, investigations into the effects of lowiron-overload in various hepatic diseases have suggestedthat iron may play a role as a cofactor in lipid peroxidationand fibrogenesis [7,13,14].
Viral hepatitisThe course of hepatitis C virus (HCV) infection may be
associated with mild-to-moderate iron overload. Manypatients infected with HCV show increased serum ferritinand iron in the liver [9]. Several factors have been sug-gested that may be important in increasing hepatic irondeposits during chronic HCV infection. Figure 2 depicts thepossible pathways of HFE and HCV synergism duringchronic hepatitis C infection [9].The HFE mutation may have a synergistic effect on iron
metabolism. Many HCV patients have an increased preva-lence of the C282Y mutation, the main mutation of HFEassociated with hemochromatosis [15,16]. HCV individuals
*Correspondence to: A. Pietrangelo, Professor for Medicine, Center forHemochromatosis, University Hospital of Modena and Reggio Emilia, Policlinico,Via del Pozzo 71, 41100 Modena, Italy.E-mail: [email protected]
Received for publication 1 October 2007; Accepted 1 October 2007
Am. J. Hematol. 82:1142–1146, 2007.
Published online 29 October 2007 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.21101
VVC 2007 Wiley-Liss, Inc.
American Journal of Hematology 1142 http://www3.interscience.wiley.com/cgi-bin/jhome/35105
who are heterozygous for HFE appear to develop morefibrosis, despite only mild increases in iron stores [17]. Theformation of free-radicals during hepatocellular iron over-load associated with hemochromatosis may have a syner-gistic effect on the pathogenesis of the viral liver disease.Non-transferrin-bound iron (NTBI) increases in patients withhemochromatosis as a result of transferrin iron saturation.NTBI is a redox-active form of iron that appears in the cir-culation of both hemochromatosis homozygotes and het-erozygotes. It has been postulated that the liver may use amechanism other than the HFE-transferrin receptor 1(TfR1) system for the uptake of NTBI during iron overload[9,18–21]. Hepatic iron storage relies predominantly on fer-ritin to sequester iron and make it catalytically inert; how-ever, redox changes in the cytoplasm, particularly inresponse to an ongoing infection, can rapidly release thisiron. The mobilized iron may become catalytically activeand generate reactive oxygen species that cause liver dam-age, and this may lead to hepatic fibrosis [9].A pathogenic effect of a mutant HFE in Kupffer cells may
also play a role in the disruption of iron metabolism as wellas in disease progression. Normally during an inflammatorychallenge, macrophages respond by increasing iron stor-age, but in hemochromatosis, macrophages do not respondin this manner. HFE mutations could modify the immuno-logical activities of macrophages during host response tobacterial and viral infection by disrupting iron-mediated reg-ulation in Kupffer cells [9]. Another explanation is that HFEin Kupffer cells synergizes with other iron proteins such asferroportin or the natural resistance-associated macro-phage protein [9]. Figure 2 depicts the possible central roleplayed by Kupffer cells in HFE/HCV disease progression[9]. A study of hepatic immunological markers by Cardosoet al. suggested that the expression of major histocompati-bility complex (MHC) class I molecules by Kupffer cells pla-ces them as probable players in the host response to HCVinfection [22].HFE might exert a still uncharacterized immunological
function. HFE is a nonclassical MHC class I molecule thatmay interact with cells of the immune system, although nodirect evidence of this has been found to date [9,23]. Onehypothesis suggests that HFE is the ligand for specific
T-lymphocytes in the intestine, coordinating both intestinalimmune response and iron uptake from the gut [9,24].Weiss et al. studied associations of macrophage activity,T-helper cell types 1 and 2 (Th-1/Th-2), iron availability, andclinical course in patients with HCV infection [25]. Theauthors reported an association between macrophage acti-vation and hepatic dysfunction. They suggest that iron sta-tus may modulate Th-1/Th-2 responses in vivo, therebyaffecting the clinical course of HCV infection [25]. Morerecently, the direct effect of iron on HCV translation [26]and replication [27] has been suggested, but the actualimplications of these in vitro observations need to beunderstood.Interferon-ribavirin therapy is an effective regimen used
to treat HCV infection. The role of iron overload and theresponse to antiviral therapy in patients with chronic HCVinfection has been debated. A few studies suggest that theremoval of iron by phlebotomy may have a beneficial effecton markers of cytolysis, oxidative stress, and fibrogenesis[28–30]. Several studies have shown an associationbetween iron overload and lower response rates to inter-feron-alpha monotherapy, which contribute to chronic HCVdisease progression [9]. However, there is still some specu-lation about whether iron overload has an effect on theresponse rate to interferon-ribavirin combination therapy. Infact, ribavirin-induced hemolysis may perturb iron statusand interfere with antiviral activity or preclude the use ofiron removal strategies. Rulyak et al. showed no differencein pretreatment hepatic iron concentration between res-ponders and nonresponders [31] to interferon-ribavirin. Sur-prisingly, Bonkovsky et al. reported that the H63D HFEmutation, which has little if any effect on iron status, wasassociated with increased early virological response (40%vs. 29%; P 5 0.0078) and sustained virological response[32]. The issue of iron chelation during hepatitis C needs tobe addressed in a large cohort of patients in carefullydesigned prospective studies.
Non-Alcoholic Fatty Liver Disease AndMetabolic SyndromeMetabolic syndrome is characterized by a core group of
interrelated disorders including obesity, insulin resistance,glucose intolerance, hypertension, and dyslipidemia. Non-alcoholic fatty liver disease (NAFLD) [33,34], which is oftenencountered in patients with the metabolic syndrome, is achronic liver disease that comprises a wide spectrum of
Figure 1. Mechanisms of cellular iron overload. 1:increased cell iron efflux; 2: altered subcellular iron traffic;3: reduced iron efflux. For each pathogenetic mechanism,examples of associated human iron loading diseases areshown. See also Ref. 1. [Color figure can be viewed in theonline issue, which is available at www.interscience.wiley.com.]
Figure 2. Scheme of possible pathways of HFE (hemo-chromatosis gene) and hepatitis C virus (HCV) synergismduring chronic hepatitis C infection [9]. Reprinted withmodification from Pietrangelo A, Gastroenterology, 2003,124, 1509–1523, � Elsevier, reproduced by permission.
American Journal of Hematology DOI 10.1002/ajh 1143
liver damage ranging from simple, uncomplicated steatosisto steatohepatitis to advanced fibrosis and cirrhosis [34].There is a strong correlation between the prevalence andseverity of NAFLD with other comorbidities of metabolicsyndrome including obesity, noninsulin dependent diabetes(Type 2), dyslipidemia, and cardiovascular disease [34].NAFLD has been shown to be an important predictor ofType 2 diabetes [35–38] and cardiovascular disease [39].Recent studies have suggested that increased iron is animportant factor in the progression from steatosis to moresevere forms of NAFLD [40,41]. HFE mutations are fre-quently found in NAFLD individuals, which presents moreevidence that iron overload is positively correlated with thedegree of hepatic injury [40]. Several studies have sug-gested that iron may be involved in the development offibrosis [42–45]. Bugianesi et al. aimed to define the rela-tive impact of iron overload, genetic mutations of HFE, andinsulin resistance on the severity of liver fibrosis in a popu-lation of patients with NAFLD [45]. The authors concludedthat ferritin levels, but not iron overload, are a marker ofsevere histological damage. Iron burden and HFE muta-tions were not significantly associated with hepatic fibrosisin most NAFLD patients in this study cohort [45]. In a sec-ond study, Fargion et al. showed that iron and glucose and/or lipid metabolism, mainly associated with insulin resist-ance, is responsible for persistent hyperferritinemia, andthat it identifies patients at risk of nonalcoholic steato-hepatitis [44].Several recent studies have also investigated the removal
of iron in NAFLD, probable diabetes, and insulin resistance.The results to date, however, have been varied and incon-clusive [8,40,46–48]. At present, treatment strategies forNAFLD are involved in prevention by modifying risk-factorsof the disease, such as calorie restriction and physicalexercise. The in vitro investigation of iron chelators hasshown that the addition of chelator improves the insulin re-sistance of hepatocytes [49]. While the in vitro data lookpromising, the effect of iron removal on insulin resistance invivo needs to be validated prospectively in NAFLD patientswith documented hepatic iron excess.
Iron ‘‘Misdistribution’’: The Ferroportin DiseaseAnd Friedreich’s Ataxia
The ferroportin diseaseFerroportin disease is a newly recognized autosomal
dominant form of hereditary iron overload [50]. This irondisorder results from a pathogenic mutation of theSLC40A1 gene. Affected patients show distinctive clinicalfeatures, such as early increase in serum ferritin in spite oflow-normal transferrin saturation, progressive iron accumu-lation in organs, and marginal anemia. In contrast to hemo-chromatosis, hepatic iron accumulation in ferroportin dis-ease occurs mainly in Kupffer cells. [50]. Some patientswith ferroportin disease have a low-tolerance to weeklyphlebotomy treatment. Less aggressive phlebotomy andadjuvant therapy with erythropoietin may be beneficial [50].The possibility exists that a specific chelator, able to prefer-entially remove iron from Kupffer cells and macrophagesand correct the ‘‘misdistribution’’ or iron, may prove usefulin the management of patients with this disorder.
Friedreich’s ataxiaA classic example of iron misdistribution with local accu-
mulation of iron in subcellular organelles is Friedreich’sataxia, the most common hereditary ataxia, which iscaused by a large expansion of an intronic GAA repeatresulting in decreased expression of the target frataxingene [51]. The signs and symptoms of the disorder (mainly
due to neurological impairment) derive from decreasedexpression of the protein frataxin, which chaperones ironfor iron-sulfur cluster biogenesis and detoxifies iron in themitochondrial matrix. Because of the ‘‘local’’ accumulationof iron, iron chelators seem effective in removing and relo-cating iron, as suggested by a recent study [52].
Other Conditions of Iron AccumulationIn addition to the examples discussed in this article, there
are several other pathologic conditions where iron excessor misdistribution may play a role and chelators may bebeneficial in the pathogenesis of these diseases (Fig. 3).Protein aggregation and oxidative stress have been dem-
onstrated as important factors leading to the pathogenesisof neurodegenerative processes in Alzheimer’s disease,Parkinson’s disease, and prion disease [53]. Changes inthe normal iron and antioxidant concentrations in the brainmaterial from patients with Parkinson’s disease have beendemonstrated [54–58]. In a 2-year, single-blind study, Crap-per McLachlan et al. investigated whether reduction of oxi-dative stress by iron chelation could slow the progressionof Alzheimer’s disease [59]. The study reported that treat-ment with deferoxamine showed a significant reduction inthe rate of decline of daily living activities. The conclusiondrawn from these results was that the sustained administra-tion of deferoxamine might slow the clinical progression ofdementia associated with Alzheimer’s disease [59].While true iron overload is not usually associated with
cancer, as an essential component for cell-cycle progres-sion and DNA synthesis, iron represents a novel moleculartarget for the design of new anticancer agents [60]. Cancercells utilize more iron than normal cells as their require-ments for ribonucleotide reductase and TfR1 are higher[61–63]. Chelation therapy is currently being evaluated as anovel approach to cancer treatment [62,63]. In addition toits role in iron overload diseases, deferoxamine also hassome potential antitumor activity. Deferoxamine acts byarresting cells at the G1/S interface, inhibiting cell-cycleprogression, and inducing apoptosis [64,65].
ConclusionBoth severe and marginal iron overload play a role in the
pathogenesis of several diseases. Iron removal studies inseveral diseases with marginal iron overload or regionaliron accumulation have shown a pathogenic role of ironand are, in some cases, valuable. The need for iron re-moval in these types of diseases is very specific and,therefore, in the future there is a need for ‘intelligent’ chela-
Figure 3. Other conditions where iron removal by chela-tion could be of potential benefit. NAFLD, nonalcoholicfatty liver disease.
1144 American Journal of Hematology DOI 10.1002/ajh
tors. In some cases, the main therapeutic goal will be theredistribution of iron toward the circulatory pool and theerythron (e.g., anemia of chronic disease, ferroportin dis-ease, and mitochondrial iron disorders); in others, removalof iron from selected sites (e.g., the liver or basal ganglia)will be the priority. As data in these types of indications arelimited, more well-designed clinical trials are warranted totest the safety and efficacy of iron chelators.
AcknowledgmentsThe author received editorial/writing support funded by
Novartis Oncology in preparation of this manuscript. Theauthor, however, is fully responsible for contents and edito-rial decisions for this manuscript.
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