Evaluation of iron overload

The effective management of iron overload requires frequent evaluation of body iron stores. Measurement of serum ferritin, although easy to perform, gives results that are too variable for the accurate prediction of total body iron. Determination of the liver iron concentration is still regarded as the best predictor of total body iron, but the procedure is invasive and has risks. Quantitative, non-invasive methods for measuring body iron are needed that are safe, accurate and readily available. At present, biomagnetic susceptometry [superconducting quantum interference device (SQUID)] is regarded as the most accurate non-invasive method for measuring liver iron, but its clinical availability is restricted. Magnetic resonance imaging (MRI) is widely available and, in principle, allows the evaluation of tissue iron in all organs that may be affected by iron overload. To date, only MRI methods for estimation of liver iron have been calibrated with tissue biopsies. Although the available methods may be improved further, clinically useful liver iron estimates can be achieved at present. Iron overload is caused by increased intestinal absorption or by parenteral iron administration as blood transfusions. Because iron excretion in humans is limited, iron accumulation from blood transfusions is predictable, providing 200–250 mg iron from each unit of blood. In contrast, iron loading caused by gastrointestinal iron absorption may be difficult to predict, and may even vary from patient to patient (Pippard, 1990). Increased intestinal absorption is caused either by augmented erythropoiesis, hypoxia (Raja et al, 1986), or by the presence of variant genes causing hereditary haemochromatosis (HH), as for example the HFE-variant (Feder et al, 1996). In the so-called iron-loading anaemias intestinal absorption may also be severely increased. In β-thalassaemia intermedia iron absorption can be up to 5–10 times normal (Pippard & Weatherall, 1984), because of an expanded, dyserythropoietic, ineffective erythropoiesis (Pippard & Weatherall, 1984; Pootrakul et al, 1988). In β-thalassaemia major hypertransfusion reduces the gastrointestinal iron absorption to 1–4 mg/d by decreasing hypoxia and the expansion of erythropoiesis (Pippard & Weatherall, 1984). Whereas excess iron caused by intestinal absorption is directed to parenchymal tissue and may cause organ damage, transfusional iron is primarily deposited in the reticuloendothelial macrophage system (RES), and is regarded as relatively harmless (Jacobs, 1977). However, iron-induced organ damage has also been reported in patients without expanded erythropoiesis, as in adult patients receiving blood transfusions for a variety of refractory, mainly hypoplastic anaemias (Schafer et al, 1981). Thus, absence of erythroid expansion is not a barrier to the redistribution of iron to parenchymal cells. The factors influencing this redistribution from the RES to parenchymal cells are not known in detail, and therefore, the associated risk of organ damage is poorly predictable. This circumstance highlights the need for a reliable estimate of the body iron content and its distribution for practical management of iron overload. Reliable measures of body iron content are especially needed in blood transfusion-dependent anaemia patients on iron chelation, to maintain a balance between the chelator's effectiveness and its toxicity, and owing to problems of compliance with iron chelation treatment (desferrioxamine) that arise frequently in the management of patients with thalassaemia (Olivieri & Brittenham, 1997). The iron status of patients with transfusional iron overload can be studied by several methods, none of which are completely satisfactory. The use of two or more indices of iron status will usually be needed to define the amount of iron and its distribution in different organs (Worwood, 1997). In general, two types of methods may be differentiated: the direct methods, based on the detection of iron within the tissue, performed either by biopsy or non-invasive methods, and the indirect tools, for example the serum ferritin concentration or iron saturation of serum transferrin. This article focuses primarily on the quantitative assessment of transfusional iron overload, but many of the conclusions may also be applied to other disorders with an increased body iron burden, e.g. HH. In unchelated transfusion-dependent patients without significant gastrointestinal absorption due either to hypoplastic erythropoiesis or to suppression by blood transfusions, a reasonable estimate of the total body iron overload can be obtained from the total number of red cells given. Transfusion requirements vary with diagnosis. In β-thalassaemia for example, provided there is effective hypertransfusion, the iron-loading rate from transfusions is 116–232 mg iron/kg body weight/year (Thalassaemia International Federation, 2000), equalling 7–14 g iron a year (body weight 60 kg). In adult patients with myelodysplastic syndromes, the iron-loading rate may vary from a few transfusions a year to eight units a month; from a few gram to 19 g iron a year (body weight 60 kg) (Jensen et al, 1996). The most accurate, and the reference method for, measurement of iron storage (Bothwell et al, 1979) is to determine the amount of stored iron that can be mobilized by repeated phlebotomies until the supply of iron for erythropoiesis is exhausted (Haskins et al, 1952). The assessment of the total body iron burden by phlebotomies is an important part of the evaluation of patients with HH, because the extent of tissue damage and survival are related to the amount of accumulated iron (Niederau et al, 1985), but is not feasible in blood-transfusion-dependent patients. The liver is the major site of iron storage in iron overload, containing 70% or more of body iron stores (Modell & Berdoukas, 1981). It is, therefore, generally accepted that the most quantitative means for determining the body iron burden in patients with iron overload, and the reference method for comparison with other is direct measurement of the liver iron concentration in a of the liver obtained at biopsy (Pippard, This is by that have a between of and total body iron stores by repeated et al, et al, Although liver biopsy is the rate is in In a liver performed in β-thalassaemia patients et al, the biopsy in only patients Measurement of the by biopsy has an of at on the is more mg and in the absence of & et al, liver biopsy is usually regarded as for the Although this is in with an that not significant in the absence of liver et al, have that can be et al, et al, et al, in the absence of clinically and significant in has been the more weight et al, In distribution of is caused by a variable amount of tissue et al, 1996). may the of from to et al, 1996). in obtained by biopsy be with et al, et al, and et al, et al, et al, that the is for of iron-induced organ damage and not only within the liver but also within the and other In on β-thalassaemia patients the of liver with the et al, 1977). from patients that the of and in patients with iron overload not until a has been et al, In the absence of liver all with a more have a concentration in patients with et al, et al, In β-thalassaemia patients on iron chelation, the has been to have The a is that of et the risk of in thalassaemia major patients been on iron chelation for or until a at weight in patients with major on iron chelation treatment with this associated with increased risk of and for the of a in transfusional iron overload has been in unchelated patients without of with (Jensen et al, In that the in normal in all patients a not treatment normal as as the The a between the and the iron excretion regarded to the iron the iron et al, & is by the of the of et al, 1985), and is regarded as the of iron in iron-induced tissue et al, The increased in to the for more an expansion of the the is a in with the serum for a direct between the of the and the extent of on patients with transfusional iron overload treatment for up to (Jensen et al, that the also to be for iron liver iron all iron estimates but as by normal or At the and the iron estimates with the but not with the the from patients the of the as the of iron in transfusional iron and the of a for an expansion of the causing and It is that the a storage or of the liver for transfusional iron, and may be that patients with liver liver may have In patients with an expanded for other ineffective the may also be to be as for example in However, the are and may only to patients with are especially in to the and clinical of a and iron chelation may be to iron chelation to an body iron in an that from chelation the of chelation It has been that a for β-thalassaemia patients on iron chelation be a that can be in patients without significant (Olivieri & Brittenham, 1997). Although the for this have been a is regarded as the best available for iron chelation, in β-thalassaemia patients Because of the risk of liver are not especially for repeated several non-invasive methods have been the can the in caused by the of iron with normal liver tissue et al, et al, et al, et al, 1990). the method has not been to be useful because of not related to the presence of iron for example, et al, and in patients with iron overload et al, et al, is to a variety of as the presence of et al, has too for iron overload et al, et al, and has not been to be clinically Magnetic measurement of iron by and The of a tissue is by the and of the in tissue by of a et al, The of iron in ferritin and is by use of a quantum interference device have between and the for in et al, and in et al, direct up to at et al, with an and the most calibrated and non-invasive method for quantitative estimation of the & The clinical of the method has been in patients with transfusional iron overload, in the evaluation of the of iron chelation with et al, in the iron chelation of and (Olivieri et al, et al, body iron by liver and iron et al, et al, and in the of the between serum ferritin and et al, et al, of the method an to iron, clinical caused by the number of in the and the of the & The of at may the more widely available at Magnetic resonance imaging (MRI) measures the tissue iron concentration by the by the presence of storage iron and on resonance of tissue This can be by the and times of et al, is as the of the usually of to distribution an applied et al, is the the usually of in a to the of the applied a that the the et al, and are by the with on the of the et al, and times may also be as the and to the of tissue by tissue iron have on ferritin but of the of ferritin and has been provided et al, iron is in different within the tissue as iron to weight as iron to as and as as ferritin or that an of the in may be even more in ferritin is in and is in et al, ferritin is has a ferritin et al, may ferritin and but only has a et al, that may the of the of ferritin is the variable iron content within the ferritin et al, as the of and may MRI the many factors that may the of iron, is from an of that the iron concentration in liver tissue and in is to the rate et al, et al, et al, et al, et al, et al, et al, but of iron for the rate et al, et al, imaging have been in few clinical et al, et al, et al, et al, et al, 1997). In the only imaging available for quantitative evaluation of tissue iron. imaging has the that of the not the because of caused by of the is by a within the this gives the but the is the the of by or imaging the an within et al, The has the imaging is to et al, 1986), the the to to of The is more to et al, and may be more to The practical of imaging is a total imaging the of an within e.g. the of or is that may the different methods for a quantitative of the tissue iron concentration from the MRI are in the of and the of the between liver tissue and a reference tissue or The method et al, owing to problems in times at causing to with et al, et al, et al, that is with with et al, The may be to a the measurement of the important in the is the of the reference tissue as an other iron, with on the of liver tissue and the reference tissue will not the However, the of reference tissue is its on the of the iron overload. Although of the tissue iron as as and of in patients with iron overload not increased iron with normal up to (Jensen et al, significant in iron be at Because of this other have as the but this is not in patients and not to the of the method et al, The use of the the patient et al, or the use of a the containing a with a et al, are methods of that a for in imaging between of iron. In of the only et al, et al, be between the and because of times improved the between and and the detection of et al, et al, but still not several have been imaging for the assessment of iron et al, et al, et al, et al, et al, et al, in quantitative estimation of have only been in two by the et al, et al, 1997). The of the imaging in is the to more because of at have also been achieved by use of and et al, et al, et al, the in et al, 1990). 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To date, few have been et al, & et al, et al, et al, et al, et al, The number of may the many problems a organ in and caused by the of the and the iron distribution may all the of the direct of the method with on is because of the risk of caused by the distribution of iron & et al, et the to patients by the from at but not significant between patients and because of the of et studied β-thalassaemia patients by use of at The patients a ferritin and a ferritin with normal only in the ferritin with liver and with the serum ferritin In a a et al, and studied but also the from in patients on only in of patients within the ferritin and only in of patients within the ferritin in of all patients and in the ferritin in the ferritin and in the normal The ferritin related to with the ferritin but only in the patients with with patients without et imaging and of The method been with of iron (Jensen et al, The evaluation of iron owing to the use and because the of the and the reference of to estimates based on the from the liver Because of important in between and between different within the even in normal an of the of the of within the performed (Jensen et al, and within the of the an at and at In of patients with anaemias the within the within the not to of blood transfusions. up to although units of blood been given. In patients up to blood of but more units of patients The related to the serum ferritin concentration the number of units of blood the iron saturation and to the to improved the with the ferritin In a on patients with transfusional iron overload at of iron chelation treatment with (Jensen et al, At the of treatment in of patients but normal in patients of treatment direct between the and the but all but of the normal or normal the of a At the and and of the and more related to the to the serum normal or normal this increased with The indirect that iron is by this a has been for estimation of iron et al, at Because of with This in a by use of a et al, the method has the that all are in the total methods with a for the of at for the method and at for the of between the methods are only available for the method et al, In a on β-thalassaemia patients on a significant between and by be et al, patients with normal normal and patients with a significant in and serum ferritin and other iron not related as in most other & et al, et al, et al, is that the method may have a different for different of iron. example, in comparison with a (Jensen et al, the may be more for of in because the method In contrast, the method may be more to iron or ferritin in iron overload owing to of the the of of the of the method the of of to of the This not with may also be to tissue factors other iron for example, in the amount of which may et al, The use of an as in the may be in this and other tissue and reference tissue are affected The method of et as as the other methods for iron are not calibrated with biopsies. Although of indices with et al, and iron et al, et al, have been only that the MRI may iron. Although reasonable to that there may be a significant between the MRI iron and the tissue iron concentration as in liver tissue for example, the of this estimation of the is results be with will be not to a reliable of a MRI method for estimation of iron with tissue because of distribution of iron the methods have to be by that the iron with of iron overload, by of the iron or by that the is a of clinical by a to survival or in direct may be obtained by the use of an The to be most to of iron overload in patients with β-thalassaemia major et al, & in a number of that iron may be by MRI because significant have been between iron and the serum ferritin concentration et al, et al, et al, et al, et al, The has been between and the in eight β-thalassaemia patients with on treatment et al, but between the results of MRI imaging and the In a the β-thalassaemia patients with transfusional iron overload on of et al, The in the patients in iron content in the et a significant between by and in β-thalassaemia patients with iron overload on et in β-thalassaemia patients that and with serum ferritin, but and not that iron is not by liver iron. the on iron and MRI that MRI indices may iron. direct of the methods with is not indirect has to be for example by a or of and of in patients with transfusional iron overload on iron chelation are The of the iron saturation of serum is a of iron status et al, The is especially useful in for HH, in which its is that of the serum ferritin et al, 1997). Thus, HH. However, the has not been to be useful for quantitative estimation of iron overload caused by blood transfusions (Jensen et al, is an iron storage of a of up to iron 1977). ferritin is by the and is by the et al, & 1996). The ferritin, stored the is by the and is not & 1996). is within the by a the iron and et al, The of and is by et al, and & and in cells by et al, 1997). The stored iron is in reticuloendothelial cells and but all other cells ferritin and a of ferritin to the that the ferritin concentration the amount of ferritin within the body et al, variety of may the between ferritin and the body iron stores. Whereas and the serum ferritin concentration et al, et al, 1986), may be increased by or et al, 1986), increased et al, liver et al, and et al, ferritin may also be increased by of tissue ferritin from liver cells or other tissue or by the of ferritin from the et al, et al, et al, et al, have the between the of iron overload and the serum ferritin concentration in β-thalassaemia patients with transfusional iron overload. In the on patients with β-thalassaemia major et al, serum ferritin with the number of units of blood and the and that units of blood and only for of the of the serum ferritin In patients receiving up to units of blood of the of serum ferritin by the number of blood units and by units of serum ferritin not with the number of units of blood. ferritin increased in patients up to but not this It that the of the serum ferritin concentration with iron stores in iron overload is a of the of iron on ferritin and the of damage on ferritin from the The of the serum ferritin in the of iron overload has also been in in patients with transfusional iron overload on iron chelation treatment by the between the serum ferritin concentration and the iron stores as by measuring the et in 19 β-thalassaemia patients that only of the in serum ferritin for by the In a in patients of the in by the serum ferritin et al, and in in patients significant be et al, In a on patients with iron overload with a et al, in in patients with transfusional iron overload the between serum ferritin and studied iron chelation (Jensen et al, a at but treatment the between serum ferritin and patients a in serum ferritin although The between ferritin and be in each patient by an The most in patients with ineffective erythropoiesis the the in patients with hypoplastic serum ferritin has been to be a for patients on iron chelation and has been to survival in β-thalassaemia patients on treatment (Olivieri et al, et al, Because serum ferritin is an with and the measurement of the serum ferritin iron concentration has been et al, 1997). It that serum ferritin iron may the body iron status by et al, 1997). In a the that in none of 19 with ferritin iron more of ferritin but this the in eight of patients with iron overload. et al, a significant between serum ferritin iron and the in patients with β-thalassaemia major and also in patients with in a the of the as a quantitative of body iron stores not be et al, significant in ferritin iron saturation be between patient with different body iron stores. The of iron in the in to parenteral administration of is related to the of body iron stores (Modell & et al, The most frequently for this has been & of the with is from of in reticuloendothelial cells in the and & It is that the of iron that is in the is the et al, Because the is to many e.g. the of the (Pippard et al, and et al, in concentration and erythroid (Pippard et al, or status (Pippard et al, is regarded as an means for the quantitative assessment of body iron stores et al, However, the of a between the iron as by the measurement of and the extent of (Jensen et al, and iron estimates (Jensen et al, obtained by MRI in patients on iron chelation with may for this of body iron. This may the and of the iron overload, more the total amount of storage iron. The of iron may also be by measuring in serum or et al, the serum is not a quantitative of total iron overload. management of iron overload requires frequent evaluation of the body iron stores. is a clinical need for non-invasive methods for measuring body iron that are safe, accurate, and readily available. ferritin although easy to has too a but at present, other is a predictor of the total body iron. The of is the best predictor of the total body iron, but the procedure is invasive and has risks. At present, the most accurate and non-invasive method for measuring liver iron, but its clinical availability is and its use is to the liver and The of may clinical in the MRI is widely and in allows the evaluation of iron overload in all organs that may be affected by iron overload. to date, only MRI methods for estimation of iron have been calibrated with iron in and clinically useful estimates can be achieved with and within a of clinical However, the MRI method has still to be to and the are needed to the and of the obtained by measuring for example or the may be is needed to the of resonance by iron overload, to the of MRI are needed the of especially for the of MRI methods for estimation of iron. the of as the has to be studied in more detail, because this may the of iron between different MRI and and the comparison of different MRI In clinical are needed in to the clinical and of iron especially a direct of the method with tissue is not