Diagnosis and management of transfusion iron overload:The role of imaging

John C. Wood*Division of Pediatric Cardiology and Radiology, Children’s Hospital Los Angeles, Los Angeles, California

The characterization of iron stores is important to prevent and treat iron overload. Serum markers such asferritin, serum iron, iron binding capacity, transferrin saturation, and nontransferrin-bound iron can be usedto follow trends in iron status; however, variability in these markers limits predictive power for any givenindividual. Liver iron represents the best single marker of total iron balance. Measures of liver iron includebiopsy, superconducting quantum interference device, computer tomography, and magnetic resonanceimaging (MRI). MRI is the most accurate and widely available noninvasive tool to assess liver iron. Themain advantages of MRI include a low-rate of variability between measurements and the ability to assessiron loading in endocrine tissues, the heart and the liver. This manuscript describes the principles,validation, and clinical utility of MRI for tissue iron estimation. Am. J. Hematol. 82:1132–1135, 2007.VVC 2007 Wiley-Liss, Inc.

IntroductionIron overload can occur among patients with hereditary

hemochromatosis, thalassemia, sickle cell disease, aplasticanemia, myelodysplasia, and other diseases. Excess ironabsorption and transfusional iron intake cause iron accumu-lation in the liver, endocrine organs, heart, and other tis-sues with severe, life-threatening consequences. Iron car-diomyopathy is of particular concern, and remains the lead-ing cause of death in patients with thalassemia major [1–4].The characterization of iron stores is, therefore, importantto prevent and treat iron overload in these patients. Imagingmodalities and other techniques available for this purposeare discussed in this article.Iron overload represents an imbalance of iron intake and

iron elimination. To appropriately tailor iron removal thera-pies, the amount of iron entering a patient’s body must alsobe considered. In thalassemia intermedia and hereditaryhemochromatosis, the progression of iron overload is mod-est and easily managed by phlebotomy or short-term chela-tion therapy. In contrast, chronic transfusion therapy deliv-ers between 0.4 and 0.5 mg/kg/day of iron. Chronic transfu-sion required in patients with severe anemia syndromesincluding thalassemia major, myelodysplastic syndromes,Diamond-Blackfan. Routine transfusion therapy is alsobeing used extensively in patients with sickle cell diseaseto prevent neurologic complications. Chronically transfusedpatients will become iron overloaded within 1 year of ther-apy and need iron chelation therapy to prevent deleteriousconsequences of iron overload. Iron chelators currentlyavailable include deferoxamine, which is administered sub-cutaneously or intravenously, and the oral chelators deferi-prone and deferasirox.Variations in transfusional requirements will also help

determine appropriate chelator dosing. This was illus-trated by a recent study in which patients treated withdeferasirox or deferiprone were grouped into three trans-fusion regimens (<7 mL/kg/month, 7–14 mL/kg/month,and >14 mL/kg/month of red blood cells). Dose-respon-siveness was observed in all three categories, but heavilytransfused patients required nearly twice as much chela-tor as lightly transfused patients in order to maintain ironbalance [5].

Serum Markers of Iron StatusSeveral serum markers can be used to follow trends in a

patient’s iron status over time. These include ferritin, serumiron, and nontransferrin-bound iron (NTBI) (Table I), as wellas total iron binding capacity and transferrin saturation(TSAT). Ferritin is the most frequently used measure as itis inexpensive, widely available, and reliable, with extensiveclinical validation in monitoring iron status. Ferritin mea-surements have prognostic value, as demonstrated byrecent studies, one of which identified cardiac-related mor-tality greater than 80% over 15 years among patients withthalassemia in whom more than 67% of ferritin measure-ments exceeded 2,500 ng/mL [6,7]. However, in individualsthe predictive value of ferritin is limited by inflammation andvitamin C deficiency. As a result, even patients with low fer-ritin levels experience elevated rates of heart disease asthey age. Furthermore, the predictive value of ferritin is notdocumented in diseases other than thalassemia, such asmyelodysplastic syndromes and sickle cell disease.

TSATNTBI appears in the blood when transferrin is highly sat-

urated so its presence can be predicted by TSAT values[8]. NTBI is toxic to the liver, heart, and other endocrine tis-sues and increased blood levels may indicate developingorgan toxicity in iron-overloaded patients. Quantification ofTSAT is readily available, however, interlaboratory assay

*Correspondence to: Prof. J. Wood, Associate Professor, Division of Cardiol-ogy, Children’s Hospital Los Angeles, Mailstop 34, 4650 Sunset Boulevard,Los Angeles, CA 90027. E-mail: jwood@chla.usc.edu

Contract grant sponsor: National Heart Lung and Blood Institute; Contractgrant number: 1 RO1 HL075592-01A1; Contract grant sponsor: GeneralClinical Research Center at Childrens Hospital Los Angeles; Contract grantnumber: RR000043-43; Contract grant sponsor: Center for Disease Control;Contract grant number: U27/CCU922106 (Thalassemia Center Grant); Con-tract grant sponsors: Novartis Pharma; Department of Pediatrics at Child-rens Hospital Los Angeles; Novartis Oncology.

Received for publication 1 October 2007; Accepted 1 October 2007

Am. J. Hematol. 82:1132–1135, 2007.

Published online 26 October 2007 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.21099

VVC 2007 Wiley-Liss, Inc.

American Journal of Hematology 1132 http://www3.interscience.wiley.com/cgi-bin/jhome/35105

variability, rapid physiologic modulation by inflammation,and nonlinearity with respect to total body iron levels limitthe practical usefulness of this measure.

Labile plasma ironNTBI is an intuitively appealing biomarker because it is

responsible for parenchymal iron loading and toxicity. NTBIassayed periodically as labile plasma iron (LPI) can beused to monitor iron overload and a patient’s response tochelation therapy. This is demonstrated by a decrease inLPI over time in thalassemia intermedia patients [9]. How-ever, data regarding the use of LPI in transfused patientsare limited, there is no standardized assay, and risky levelsof LPI have yet to be identified.Overall, NTBI levels differ considerably between assay

methods. One study identified coefficients of variation rang-ing from 4 to 193% between tests, with differences due pri-marily to procedural variations, iron contamination, and var-iation in NTBI isoforms [8].

Liver IronLiver iron levels accurately reflect total body iron stores

because the liver is the dominant iron storage organ[10,11]. Liver iron levels have also been used to estimaterisk, and predict outcomes such as liver failure, diabetes,heart failure, and death [7,12]. Methods for quantifying liveriron include biopsy, use of the superconducting quantum in-terference device (SQUID), computed tomography (CT),and magnetic resonance imaging (MRI).

Liver biopsyLiver biopsy is the only direct assessment of liver iron

and remains the standard of care in institutions withoutaccess to noninvasive surrogate techniques for iron mea-surement. It allows the assessment of liver histology, whichis important in staging liver fibrosis, particularly in hepatitisC positive patients. In adults, liver biopsy can be performedas an outpatient procedure. However, liver biopsy is expen-sive and carries a 0.5% risk for serious bleeding [13]. Post-procedure discomfort limits patient acceptance and sam-pling variability of the procedure is relatively high at 12–15% overall, and up to 40% among patients with cirrhosis[14,15].

Non invasive techniques to measure liver iron: SQUID,CT, and MRISQUID was among the first noninvasive techniques used

to measure body iron loading [16]. Its limitations includehigh installation costs, limited availability, and limited utilityas it measures only liver and spleen iron content. In addi-tion, validation data for SQUID are limited.CT is well-tolerated by patients and relatively inexpen-

sive, so it has the potential for wide clinical use. However,application of this technique has been critically limited by

lack of validation in humans, poor sensitivity in patients withlow iron loads, and exposure to ionizing radiation.Although the principles of using MRI for detection of iron

have been known for the past 20 years, this technologyhas only recently become reproducible and routine for themeasurement of iron in the liver and heart. MRI measuresiron content in all organs, is widely available, and has beenvalidated for measuring liver iron content. Recently, a speci-alized application of MRI (Ferriscan1, Resonance Health,Australia) was approved by the Food and Drug Administra-tion for the measurement of liver iron. MRI limitationsinclude expense, the need for trained personnel for acquisi-tion and postprocessing, and the necessity of standardizingthe technique prior to its implementation.To measure hepatic iron concentration, an MRI scanner

transmits a radio stimulus that excites water protons in he-patic tissue. Free diffusing water protons experience varia-tions in the magnetic field produced by iron particles withinthe liver. Iron causes MRI images to darken at a rate pro-portional to the hepatic iron load, with the half-life of thisdarkening defined as T2*. The rate of darkening, desig-nated as R2*, is the reciprocal of T2* and is proportional tothe iron content of the tissues. MRI scanning estimates tis-sue iron concentration both by gradient echo imaging,which provides T2*, and spin echo imaging, which providesT2, the reciprocal of R2 [17].Two studies have compared the amount of iron measured

at liver biopsy to measurements of R2 and R2* with MRI. Thefirst study measured R2 and identified a strong nonlinear rela-tionship between R2 and hepatic iron concentration (Fig. 1)[18]. In the second study, MRI measurements of both R2*andR2 with MRI showed good correlation with liver biopsy andinterexam reproducibility was acceptable at 3–8% [17].An important advantage of MRI is the low-rate of variabil-

ity (typically 5–7%) between hepatic iron measurements,which is not attainable by liver biopsy. Therefore, MRI is agood noninvasive method for long-term monitoring of liveriron concentrations during chelation therapy. Anotheradvantage of MRI is its ability to quantify iron loading in theheart and other endocrine tissues, which may occur in clini-cally significant amounts even during adequate chelation.Cardiomyopathy is the most harmful manifestation of

transfusional iron overload [3]. Once cardiac symptoms de-velop, decompensation and death occur rapidly unless che-lation therapy is intensified [1,4]. Cardiac iron is removedslowly from the myocardium, a factor that contributes to thehigh-mortality of patients with cardiomyopathy, even in thepresence of intensive chelation [19]. MRI evaluation of car-diac iron can help predict cardiac risk [19]. A study showedthat patients with T2* > 20 msec (no detectable cardiaciron) do not typically develop heart dysfunction, whilepatients with T2* < 10 msec are at a proportionally higherrisk for cardiac dysfunction [19].R2* exhibits a linear relationship to heart iron according

to data from animal studies [20]. In addition, although stor-age patterns of iron in the heart and in the liver were differ-ent, the MRI calibration for an R2* technique does not differsignificantly [20]. While human data on the correlationbetween R2/R2* and cardiac iron are limited, existing find-ings show that both R2* and R2 demonstrate a linear cor-relation of R2*, with the iron in cardiac tissue [21].Liver iron concentrations correlate poorly with those in

cardiac tissue because the mechanisms of iron uptake andclearance differ between organs. In particular, iron is de-posited and removed more quickly from the liver than fromcardiac tissue, creating hysteresis between measured ironlevels in these tissues. Many patients, particularly adoles-cents, can have high liver iron without detectable cardiaciron. If this situation exists long-term, cardiac iron begins to

TABLE I. Serum Markers of Iron Status

Ferritin Serum iron NTBI

Availability 1111 111 1

Cost Low Moderate Variable

Reliability 11 11 Variable

Clinical

validation

111 1 1

Greatest

weakness

Inflammation,

false negative

Nonlinear,

method-dependent

No standard,

unproven

NTBI, nontransferrin-bound iron.

American Journal of Hematology DOI 10.1002/ajh 1133

accumulate, even in the absence of additional hepatic ironloading. Conversely, intensive chelation can clear iron fromthe liver fivefold more quickly than the heart. Therefore, apatient may have high cardiac iron despite a lower totalbody iron burden following chelation therapy.While high liver iron is clearly a risk factor for cardiac

iron accumulation, it is important to recognize that there isno hepatic iron concentration at which cardiac iron deposi-tion does not occur. Two patient cases illustrate this point,both of whom were compliant with chelation therapy andpresented initially without cardiac iron by MRI (Fig. 2) [17].The first patient had an initial liver iron level of 5 mg/g dryweight that increased to 7 mg/g dry weight, while thepatient’s cardiac iron concentration tripled over the sametime period. The second patient had an initial liver iron of2 mg/g dry weight that decreased to 1 mg/g dry weight buthad detectable cardiac iron 1 year later despite chelationtherapy. These cases emphasize that there are mecha-nisms other than overwhelming iron saturation of the liver,that lead to cardiac iron loading.

Monitoring GuidelinesAll patients on chronic transfusion therapy require serial

monitoring of iron stores. A logical paradigm for monitoringbody iron loading in these patients is to measure ferritinlevels at least quarterly, and iron panels once each year(Table II). Liver iron should be measured annually (eitherby biopsy or noninvasively), plus every 3–6 months inpatients who are intensively chelated for heart failure. IfMRI techniques are available, cardiac iron and cardiacfunction should also be measured by MRI yearly, plus every6 months in patients chelated intensively.

ConclusionBlood transfusion burden is an important measure of

total body iron balance. Ferritin is a relatively inexpensiveand widely-available measure, useful in monitoring chela-tion therapy. LPI measurements show promise for predict-ing endocrine and cardiac iron toxicity, although existingLPI assays require more refinement, standardization, andclinical validation. Liver iron concentration reflects totalbody iron stores, but incompletely stratifies the risks of ironoverload complications. MRI offers the most accurate andwidely available noninvasive tool for assessing liver ironconcentration. As barriers to broad implementation of MRIare overcome, comprehensive MRI assessment of liver,

and cardiac iron and cardiac function is likely to becomethe standard of care in iron overload.

AcknowledgmentThe author is fully responsible for contents and editorial

decisions for this manuscript.

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Figure 1. The relationship between R2 on the right sideof the liver and needle biopsy iron concentrations [18].This research was originally published in Blood. St PierreTG, et al. Noninvasive measurement and imaging of liveriron concentrations using proton magnetic resonance.Blood 2005;105:855-861. � the American Society of Hema-tology. [Color figure can be viewed in the online issue,which is available at www.interscience.wiley.com.]

Figure 2. Iron trajectories of two patients. Scattergramdemonstrating cardiac iron versus liver iron (HIC) in twopatients who developed cardiac iron loading despite hav-ing apparently adequate iron chelation [17]. Figureadapted from Wood JC. Magnetic resonance imaging mea-surement of iron overload. Curr Opin Hematol 2007;14:183-190 with permission from Lippincott Williams andWilkins.

TABLE II. Iron Status Monitoring Paradigm

Serum markers Liver iron Cardiac iron

Ferritin: at least

quarterly

Annually Annually

Complete iron

panels: annually

Every 3–6 months

if intensively chelated

Every 6 months if

intensively chelated

1134 American Journal of Hematology DOI 10.1002/ajh

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