Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)
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Transfusional iron overload and chelation therapy withdeferoxamine and deferiprone (L1)
George J. Kontoghiorghes *, Katerina Pattichi, Michael Hadjigavriel,Annita Kolnagou
Postgraduate Research Institute of Science, Technology, Environment and Medicine, 3 Ammochostou St, Limassol 3021, Cyprus
Iron is essential for all living organisms. Under normal conditions there is no regulatory and rapid iron excretion in
humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood transfusions
in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This
excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically
transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs
deferoxamine (DF) and deferiprone (L1). Eective chelation therapy in chronically transfused patients can only be
achieved if iron chelators can remove sucient amounts of iron, equivalent to those accumulated in the body from
transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both
chelating drugs have to be administered almost daily and at high doses. This form of administration also requires that a
chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the
last 40 years. It is mostly administered by subcutaneous infusion (4060 mg/kg, 812 h, 5 days per week), is eective in
iron removal and has low toxicity. However, less than 10% of the patients requiring iron chelation therapy worldwide
are able to receive DF because of its high cost, low compliance and in some cases toxicity. In the last 10 years we have
witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional
iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000
patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a
negative iron balance at doses of 50120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels
and reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible
increased risk of toxicity, all the toxic side eects of L1 are currently considered reversible, controllable and man-
ageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%)
and zinc deciency (1%). The incidence of these toxic side eects could in general be reduced by using lower doses of L1
or combination therapy with DF. Combination therapy could also benet patients experiencing toxicity with DF and
those not responding to either chelator alone. The overall ecacy and toxicity of L1 is comparable to that of DF in
both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations
are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and
by identifying new applications in other diseases of iron imbalance. 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Oral chelators; Iron overload; Deferoxamine; L1; Deferiprone; Thalassaemia
Transfusion Science 23 (2000) 211223
* Corresponding author. Tel.: +357-5734615; fax: +357-5395926.
E-mail address: firstname.lastname@example.org (G.J. Kontoghiorghes).
0955-3886/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved.PII: S 0 9 5 5 - 3 8 8 6 ( 0 0 ) 0 0 0 8 9 - 8
1. Iron imbalance
Iron is an essential trace element found in manyproteins, which play a key role in the metabolicpathways involved in the growth and developmentof humans and almost all other organisms. Undernormal conditions total body iron in adults isabout 4.5 g and is uniformly distributed as hae-moglobin (2.6 g), myoglobin (0.4 g), non-haemstorage iron in tissues (1.4 g), smaller amounts asenzymes and minute amounts in plasma. About14 mg of dietary iron is absorbed daily mainly fromthe duodenum and equivalent amounts are lostfrom various parts of the body. Body iron levelsare regulated by the gut through the absorption ofiron from the diet and by the erythropoietic ac-tivity of the bone marrow. Increased iron ab-sorption is observed with increased erythropoieticactivity, for example in conditions with ineectiveerythropoiesis. The essential need for iron has re-sulted in the evolution of homeostatic regulatorymechanisms for the preservation, storage anddistribution of this metal in humans but not itsrapid excretion or detoxication when in vast ex-cess in the body. Under normal conditions theintracellular uptake and storage of iron are regu-lated by the iron regulatory proteins (IRPs)through the translational control of the synthesisof the transferrin receptor and intracellular ferr-itin. The intracellular storage of iron is primarilyaccomplished by the intracellular proteins ferritinand haemosiderin. Following absorption, thetransport of iron in blood is accomplished bytransferrin and into the cells by the binding of twomolecules of mono- or diferric transferrin to atransferrin receptor on the cell surface and subse-quent incorporation in the cell within an endo-some. Iron release from transferrin in theendosome intracellularly is accomplished by acid-ication of the endosome from pH 7.4 to 5.6. Innormal individuals transferrin in plasma is satu-rated 2535% with iron. Iron imbalance in thebody may lead to many complications. Iron de-ciency is the most common abnormality in relationto iron metabolic disorders aecting almost allpopulations, certain ages and both sexes. In thiscondition the amount of iron entering the body islower than the amount lost from the body.
Many dietary and other factors can aect ironuptake and distribution in the body. For example,vegetarian diet low in iron can in general result iniron deciency, whereas in conditions such as theanaemia of chronic disease iron is diverted to thereticuloendothelial system. Similarly, some drugscan cause abnormal body distribution of iron.
In iron overload, body iron levels increaseabove normal because the amount of iron enteringthe body is higher than the amount leaving thebody. Excess amounts of iron can enter the bodymainly because of increased intestinal iron ab-sorption, e.g., in hereditary haemochromatosis, orbecause of red blood cell transfusions. In bothcases, the rate of iron loading and total body ironlevels are critical for the early manifestation ofiron toxicity.
2. Transfusional iron overload in thalassaemia and
Transfusional iron overload is the most com-mon metal-related toxicity condition with thehighest mortality rate worldwide. The risk ishigher in those belonging in the category of themost common inherited disorder namely the hae-moglobinopathies. It is estimated that 270 millionpeople are heterozygotes of a haemoglobinopathyand at least 200 000 babies are born each year, halfwith sickle cell disease and the other half withthalassaemia . About 73% of those born withthalassaemia could potentially develop iron over-load and toxicity from transfusions and/orincreased iron absorption. In particular, b-thalassaemia major accounts for 40% of births andhas a high mortality rate if regular red blood celltransfusions are carried out but no chelationtherapy is available. HbE/b-thalassaemia whichaccounts for 30% of births has a lower risk withrespect to iron overload and toxicity because ofless severe anaemia and a slower rate of iron ac-cumulation from increased iron absorption and/ortransfusions. b-Thalassaemia major patients areunable to make normal red blood cells and canonly survive if they receive regular red blood celltransfusions every two to six weeks. Withoutblood transfusions they die within 4 years from
212 G.J. Kontoghiorghes et al. / Transfusion Science 23 (2000) 211223
birth. The mean life span of transfused red bloodcells is about 60 days. Usually the rate of red bloodcell transfusions is designed in each patient so as tomaintain haemoglobin levels preferably above11 g/dl. Each unit of blood transfused contains 200250 mg iron and the average daily body intake ofiron as haemoglobin in adult patients is 2530 mg.This amount of iron is released daily into theplasma from the breakdown of eete red bloodcells by the reticuloendothelial system mainly ofthe spleen and the liver. The iron released in theplasma from the transfused eete red blood cellscannot be reutilised in iron-overloaded patients. Itis transferred by transferrin, or if transferrin issaturated with iron it nds its way and is eventu-ally stored intracellularly in the form of ferritinand mostly as haemosiderin in various organs suchas the liver, the pancreas, the endocrine and theheart. In transfused patients serum transferrin ironsaturation increases to a variable degree abovenormal and in most cases exceeds 100% followingthe transfusion of less than 50 units of blood. Atthis stage, non-transferrin bound iron (NTBI) iscirculating in the plasma and because tissue irondistribution is no longer primarily regulated bytransferrin it may result in variable tissue distri-bution and toxicity.
The provision of regular red blood cell trans-fusions and iron chelation therapy is able toachieve normal growth and development in b-thalassaemia major patients and some of thesepatients have now reached their fourth decade oflife. Iron chelation therapy in such patients shouldbe introduced by the 23rd year of life if perma-nent organ damage due to iron overload andtoxicity is to be avoided. Regular red blood celltransfusions and iron chelation are the main formof therapy for b-thalassaemia patients (over 99%),while other forms of treatment such as bonemarrow transplantation account only for less than0.1%.
The incidence and distribution of thalassaemiaare mainly in developing countries, where carriersor heterozygotes account for 110% of the popu-lation (e.g., India) or in other countries such asCyprus it is as much as 16% of the population .Due to inadequate health resources, most of thecases of thalassaemia are not diagnosed or treated
in developing countries. However, despite the lowprognosis of thalassaemia the number of transfu-sion centres in such countries is expanding and as aconsequence the number of iron-loaded patientsand the need for chelation therapy have substan-tially increased. In contrast to reality, because ofthe small number of thalassaemia patients in Eu-rope and North America, thalassaemia is regardedas an orphan disease and the drugs for its treat-ment as orphan drugs.
Transfusional iron overload and the associatedcomplications could also be developed in manyother conditions in addition to the thalassaemias,such as in sickle cell anaemia, myelodysplasia,myelobrosis, aplastic anaemia, sideroblasticanaemia, pyruvate kinase deciency, BlackfanDiamond anaemia, Fanconis anaemia, hereditaryhypochromic anaemia, liver disease, porphyriacutanea tarda, haemodialysis, cancer, etc. .
3. Iron toxicity mechanisms
In all the conditions of iron overload, irontoxicity may arise mainly from the incapacity ofcells to store iron in a safe storage form, resultingin lysosomal rupture and subsequent cellular andtissue damage. Potentially toxic forms of iron iniron overload are the low molecular weight labileiron pool and haemosiderin found intracellularlyand the low molecular weight non-transferrinbound iron (NTBI) found extracellularly. Ironcould catalyse the oxidative breakdown of mostbiomolecules such as lipids, sugars, amino acids,DNA etc. . Deposition of excess iron in cells andorgans coupled together with the breakdown ofantioxidant controls and of other controls relatedto iron regulatory mechanisms can also result inmolecular, cellular and tissue damages.
Clinical abnormalities are usually manifestedfollowing the transfusion of 50100 units of redblood cells, which is equivalent to 12.525 g ofstorage iron in the body. Such abnormalities in-clude liver and spleen enlargement associated withexcessive red cell destruction and iron deposition,damage to pancreas resulting in diabetes mellitus,damage to the endocrine organs, resulting ingrowth failure and delayed or absent puberty, joint
G.J. Kontoghiorghes et al. / Transfusion Science 23 (2000) 211223 213
pains, infections and nally cardiac damage, whichmay lead to cardiac arrhythmias and congestiveheart failure. The last abnormality is the mostcommon cause of death in b-thalassaemia majorpatients, which occurs by the second decade oflife especially in those not receiving chelationtherapy .
4. Methods for the assessment of iron overload
Estimation of the body iron status and theprogress of iron chelation therapy in iron-loadedpatients could be achieved by a variety of methods,all of which have limitations and none of whichcould precisely predict total body iron and extentof iron toxicity. This is mainly because of vari-ability in body and organ iron distribution, irondetection methods, iron estimation and extrapo-lation to all other body iron pools and other fac-tors such as the diet, infection, inammation,erythropoietic activity, etc. The most common andindirect methods for estimating body iron statusare serum ferritin, transferrin iron saturation andurinary iron excretion in response to chelatingagents such as DF, L1 and DTPA. The most ac-curate but invasive method of body iron determi-nation is iron estimation and histochemistry of aliver biopsy, which could identify the non-haemiron concentration and the level as well as thepattern of iron deposition in hepatocytes andKuper cells, thus reecting total body iron load.A non-invasive method of liver iron estimationwhich is gaining ground in the diagnosis of ironoverload is SQUID-biosusceptometry, which cor-relates well with results from liver biopsies. Mag-netic resonance imaging (MRI) techniques are alsobecoming useful tools for assessing dierentialorgan iron deposition and in particular heart ironload which is critical for the prognosis of iron-loaded patients. Another indirect parameter forassessing potential iron toxicity rather than ironoverload is NTBI, which usually appears whentransferrin is fully or nearly fully saturated withiron. All the above methods could be used peri-odically for assessing the prognosis of the patients,which is directly related to their body iron loadand organ function as well as for the adjustment of
the dose protocol during iron chelation therapy. Inaddition to the regular clininical and biochemicalmonitoring, serum ferritin or urinary iron estima-tions every three months and liver iron estimationannually from liver biopsies or by using SQUID-biosusceptometry or by other methods could besucient for monitoring the iro...