British Journal of Haematology, 1983, 54, 503-507

Clinic a1 Annotation

THE MANAGEMENT OF IRON CHELATION THERAPY

Iron overload is associated with tissue damage particularly affecting the heart, liver and endocrine organs. In hereditary idiopathic haemochromatosis removal of iron by venesection has been shown to reduce liver fibrosis and improve cardiac function and life expectancy. However, in iron loading anaemias, notably the thalassaemia syndromes, in which regular blood transfusions or excessive gastrointestinal iron absorption lead to a progressive accumulation of iron, venesection is clearly not feasible, and attention has therefore been focused on the use of iron chelating agents.

Desferrioxamine therapy

Desferrioxamine (DF), a hydroxamic acid derivative of Streptomyces pilosus, was introduced in 1963 and is the only iron chelator in current clinical use. It has the great advantage of being remarkably specific for iron, but it is poorly absorbed when given by mouth and has to be given parenterally for maximal effect.

A controlled trial of DF treatment in transfusion dependent thalassaemic children was started at Great Ormond Street Hospital, London, in the 1960s (Barry et al, 1974). Long-term follow up showed that the progress of liver fibrosis was arrested in children receiving regular intramuscular injections of DF even when given in what would now be regarded as inadequate dosage. A retrospective study of a much larger group of patients has suggested a small, but significant, increase in life expectancy in children receiving such intramuscular DF (Modell et aI, 1982).

However, the use of DF was not widely accepted until Propper et aZ(1976) demonstrated the superiority of continuous infusions of DF as opposed to bolus injections in enhancing urinary iron excretion. This has been confirmed in several other studies and where some means is provided for this extremely expensive form of therapy (1 g of DF costs over €3), 8-12 h subcutaneous infusions of DF on 5-6 nights each week has become standard treatment. These are usually administered via a narrow gauge (e.g. 26g) needle inserted in the anterior abdominal wall and connected to a battery powered syringe driver (Wright & Callan, 19 79). It should be recognized, however, that the clinical benefit of this approach has yet to be fully demonstrated: the reduction and even complete removal of excess hepatic iron stores has been shown together with improvement of liver function (Hoarand et al, 1979), but subcutaneous DF may be less effective in reversing or preventing cardiac damage in patients with established iron overload (Propper et al, 1982). The crucial question as to whether treatment started in infancy will permit normal growth through puberty as well as prolonged Correspondence: Dr M. J. Pippard, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU.

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504 Clinical Annotation

survival requires longer term clinical trials. Because subcutaneous DP is expensive and inconvenient for the patient and their families we regard this as 'stop-gap' treatment given in the hope of keeping patients in good clinical condition until more effective oral iron chelation therapy is available.

Which patients need chelation therapy?

There is no doubt about the life-threatening risk of iron overload in transfusion-dependent congenital anaemias, such as thalassaemia major and congenital red cell aplasia. The risk in patients loading from excessive food iron absorption may be more difficult to determine. This group includes patients with fl thalassaemia intermedia (including Hb E/P thalassaemia double heterozygotes), who form a considerable clinical problem in many parts of the world where thalassaemia is frequent, as well as patients with less common congenital or acquired dyserythropoietic anaemias (e.g. the sideroblastic anaemias). The extent of erythroid expansion and the age of the patient may together be useful in predicting the risk of iron loading (Peto et al. 1983). and a raised serum ferritin level may provide indirect evidence of iron overload. However, it is not yet certain that this assay will detect early iron overload in these anaemias, and where there is liver damage very high serum ferritin levels do not necessarily retlect iron stores. A liver biopsy to assess iron load and tissue damage may therefore be essential before considering long-term treatment.

In sickle cell disease it is unusual to run into problems of iron toxicity. Even in patients transfused frequently to suppress sickle haemoglobin production, the degree of risk from iron damage is not well defined. Chronic inflammation associated with sickle cell disease may help to keep excess iron in macrophages (where it is probably both relatively non-toxic and unavailable to DF) rather than in parenchymal cells such as hepatocytes, from which it would be readily chelated. Patients with sickle cell disease suspected of iron overload should therefore be individually assessed and may require a liver biopsy to determine the cellular distribution of the iron.

In patients with acquired transfusion-dependent anaemias (e.g. sideroblastic anaemias or myelofibrosis) signs of iron toxicity may occur within the first 2 or 3 years of regular transfusion therapy (Schafer et al. 1981 ), but in most cases the progressive, life-threatening nature of the underlying disorder will argue against the addition of a cumbersome and as yet incompletely proven therapy.

Planning the iron chelation therapy

In the congenital iron loading anaemias, how early should treatment be started? As iron damage may be present from infancy, prevention of iron loading should be the aim. Even in very young children a net iron excretion can be obtained with subcutaneous infusions of DF and ideally treatment should begin between the ages of 2 and 4 years. The question of dosage has been the subject of a number of investigations in most of which only the urinary iron excretion in response to DF has been measured. There are two inherent difficulties in this approach. First, the proportion of iron excreted in the urine is variable, being maximal

Clinical Annotation 505

immediately before transfusion and reduced, in association with the suppression of erythropoiesis, after transfusion. Secondly, the proportion of iron excreted through the bile into the gut is not measured. This has been found to vary reciprocally with the urinary iron throughout the transfusion cycle, and there is thus less variation in total iron excretion in response to DF than is suggested by the urinary measurements alone (Pippard et al, 1982).

Because of the practical difficulties in measuring faecal iron excretion estimation of the dose required must depend on urinary iron measurements in response to varying doses of DF. However, such dose/response assays should be carried out at a standard time in relation to transfusion, preferably just before a transfusion is due when the faecal excretion will be at a minimum. The urinary iron may be measured directly by atomic absorption spectrophoto- metry, or by a colourimetric assay, such as that based on the ICSH recommended method for serum iron determinations (Pippard & Stray, 1982).

In young children (less than 6 years old ) there is little increase in urinary iron excretion above a dose of 1 g DF given over 12 h (Pippard et al, 19 78) . Hence a dose within the range of 0.2 5 -1 g DF is usually suitable for this age group. In children presenting at an older age the plateau in urine iron excretion is not usually achieved below a dose of 2 g per 12 h subcutaneous infusion. In heavily iron laden subjects doses up to 4 g may give a linear response. It should be remembered that reassessment of the most effective dose should be made every year or two and the dosage adjusted accordingly, care being taken to standardize the conditions under which the measures are made (see above).

Recently it has been found that the amount of iron in the faeces forms a steadily larger proportion of the total iron excretion as the dose of DF is increased. In some cases it may greatly exceed that found in the urine with a total iron loss amounting to several hundred milligrams a day (Pippard et al, 1982). This has suggested that intensive use of continuous large dose infusions may deserve a trial in patients with established cardiac dysfunction in an attempt to achieve rapid removal of the toxic iron load. In addition, less frequent infusion of large doses of DF (e.g. 150 mg/kg over 24 h) in place of the usual 1-2 g 5-6 nights per week, might be an alternative method of obtaining negative iron balance which could be more acceptable to some patients. There is clearly potential for modification of treatment schedules to suit particular clinical situations and patient temperament, but there is also a need for further work on the mechanisms of iron toxicity, since it is not clear whether it is the total iron load or a more labile, chelatable, intracellular iron pool that is of prime importance. The effects of the latter might be more effectively controlled by the frequent use of subcutaneous infusions to ‘cream-off the toxic fraction of iron from the tissues, rather than occasional large doses, even though the latter might achieve the same reduction in total iron load.

Ascorbate supplements

There is no question that repletion of the ascorbate deficiency which is common in states of iron overload increases the amount of urinary and, to a lesser extent, stool iron excretion in response to DF. However, ascorbate may increase the amount of labile and potentially toxic iron within tissues, as well as mobilizing iron from macrophages to a relatively more dangerous site in the parenchymal tissues. Indeed cardiac decompensation has been reported

506 Clinical Annotation when large doses of ascorbate were given to heavily iron-laden thalassaemic subjects (Nienhuis, 198 1). This does not, however, appear to be a problem when the dose is confined to not more than 100-200 mg of ascorbic acid given during DF treatment. The dose should be given in the evening and separate from meals so as not to enhance absorption of iron from food.

Adverw reactions

Are there any toxic effects directly related to the DF.> Provided the infusions of DF are given deep in the subcutaneous tissues, using a solution no more concentrated than 0 .5 gin 2 ml of water, local erythema and tenderness can be kept to a minimum. Very occasional cases of an anaphylactic drug reaction have been reported, one of which was subjected to successful desensitization with steadily increasing doses of the drug (Miller et al, 1981). In early animal experiments cataracts developed with continued exposure to high doses, and this has led us to advise at least an annual ophthalmic examination of patients receiving subcutaneous DF. Although cataract formation has been reported in man after intramuscular injections of the drug, this is an extremely rare occurrence and we have not seen this with subcutaneous infusions. More recently, problems with dark adaptation of vision have occurred in a few patients. The mechanism and significance of this are not yet clear, but this finding emphasizes the need for regular eye examinations. In some patients, particularly teenagers, there may be problems of compliance with the therapy. Others may feel that for the f is t time they are in command of their disease and an increase in self-assurance has accompanied regular use of the pump.

Monitoring treatment

How is the effectiveness of this therapy to be judged? This is not an easy problem since indirect measurement of iron stores using a serum ferritin assay is influenced both by the degree of tissue damage and the level of iron stores. Improvements in liver function may, at least in part, be responsible for the rapid fall in serum ferritin seen in some patients soon after starting subcutaneous DF. Conventional measurements of cardiac function including echocardiogra- phy have been disappointing in charting the progress of heavily iron loaded patients, and careful long-term clinical observations, particularly simple measurements of growth, are likely to be as important as any more detailed laboratory investigation.

Conclusion

The clinical and laboratory studies with DF to date have suggested that it may be feasible to overcome the problem of transfusional iron overload at the price of a considerable investment of money (in the infusion pump and drug) and of time and inconvenience for the patient and/or his family. Subcutaneous DF is clearly only an interim and partial solution to the problem, and the search for new, orally effective, iron chelating agents, reviewed in these columns by Jacobs (1979). needs to continue. Such a drug would have an enormous market

CZinicaZ Annotation 507

on a world scale, for even if prevention programmes for the more severe forms of thalassaemia become more effective and widespread there will still be a place for an oral iron chelating agent in the treatment of the milder forms of f i thalassaemia. At the moment, the expense of the DF treatment and the variable response between patients means that each patient should have a careful individual approach to planning and monitoring their therapy with particular attention to the dose and frequency of infusion needed to achieve a net iron loss.

Nufield Department of Clinical Medicine, John RadcliKe Hospital, Oxford

M. J. PIPPARD S. T. CALLENDER

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