479
Mediterranean, the Middle East, and the Far East, but now that treatment with regular blood-transfusions is becoming common in many of these areas, transfusional iron overload has been promoted to an important cause of death among adolescents. Desferrioxamine remains the only widely available drug for treating transfusional iron overload. Unfortunately it is expensive, being a complex hyd-
THE LANCET
Desferrioxamine and Transfusional Iron Overload CHRONIC subcutaneous infusion of the iron-che-
lating drug desferrioxamine, an imaginative new approach to the control of transfusional iron-overload,’-3 confronts the clinician with difficult scientific and ethical decisions. Transfusional iron overload is the consequence of regular blood-transfusion for refractory anaemia. Children with thalassaemia major are by far the largest group of such patients, though a sizeable second group is made up of children with erythrogenesis imperfecta, aplastic anaemia, and severe sickle-cell disease, and of adults with, for instance, sideroblastic anxmia and myelofibrosis. A transfusion-dependent patient usually receives an average of 0.3 mg of iron per kilogram per day intravenously as blood-i.e., from 3 mg daily in a 10 kg child to 21 mg daily in a 70 kg man. There is no significant excretion of iron. The natural history of iron overload among children with thalassxmia major is now well understood.4 There are no clinical signs until the age of 11 years, but then growth usually slows owing to endocrine disturbances; subsequently failure of puberty is common, and cirrhosis, hypoparathyroidism, and diabetes may follow : patients die of refractory cardiac failure, usually heralded by arrhythmias, at age 16-22. Thus, iron does not cause serious symptoms until the body iron load has risen to more than 20 g (the equivalent of 100 units of blood), and death occurs at a load of about 60 g (the equivalent of 300 units). There may also be a time factor-in other words, a smaller iron load over a longer period may produce similar complications, so an accumulated iron load of more than 10 g is cause for anxiety. The natural history of adult transfusional haemosiderosis is less well described, but the above figures fit well with the pathological data of BUJA and ROBERTS5 showing that serious iron loading in the heart starts at a transfusional load of 100 units. Thalassxmia major used to be one of the major causes of infant mortality in some parts of the 1.
Propper, R. D., Shurin,
S. B., Nathan, D. G. New
Engl. J.
Med. 1976,
294,
1421. 2.
roxylamine produced by
a
Streptomyces
grown in
culture. The colourless drug is injected parenterally ; it combines with iron, probably in the liver parenchymal cells,6 and the rust-coloured iron complex is excreted, about two-thirds in the urine and one-third in the stool.’ Most investigators have measured only the urinary component of the iron excretion. The response to the drug is related, with wide individual variations, to the body iron load88 and is enhanced by ascorbic acid given orally.9,10 A standard intramuscular injection of 500 mg of desferrioxamine removes less than 1 mg of iron from a normal adult or a 1-year-old child with thalassaemia, but in response to the same dose the average 8-year-old with thalasssemia excretes 8 mg of iron in the urine, which is the equivalent of the amount he receives each day as blood. The average 13-yearold excretes 17 mg, which is substantially more than his average daily intake as blood .4, 11 The response is maintained if the drug is given daily, so that the 8-year-old can be brought into iron balance and the 13-year-old into negative balance by intramuscular injection of a weight-related dose of 0.5-1.5g per day. However, the iron load at which balance seems to be achieved is about 15 g, as opposed to the normal stores of 1 g, and if such a large load remains toxic the treatment will achieve very little. Happily, intramuscular desferrioxamine does seem to protect the liver,12 and also the heart,l3,a from the damaging effects of iron. Desferrioxamine has now been used as chronic treatment for over 10 years with few unwanted effects; very rarely, it causes reversible cataracts. Thus, the results with intramuscular desferrioxamine are encouraging but necessarily incomplete, because, owing to the slow evolution of the condition, information about the drug’s effect on long-term survival cannot be obtained for many years. Even so, 2 years ago many clinicians felt that the evidence was already strong enough to warrant regular intramuscular desferrioxamine in all transfusion-dependent patients, and the general vat
Hussain, M. A. M., Flynn, D. M., Green, N., Hussein, S., Hoffbrand, A. V. Lancet, 1976, ii, 1278. 3. Pippard, M. J., Callender, S. T., Weatherall, D. J. Clin. Sci. mol. Med. 1978, 54, 99. 4. Modell, B. Archs Dis. Child. 1977, 52, 489. 5 Buja, L. M., Roberts, W. C. Am. J. Med. 1971, 51, 209.
Hershko, C., Cook, J. D., Finch, C. A. J. Lab. clin. Med. 1973, 81, 876. Cumming, R. L. C., Millar, J. A., Smith, J. A., Goldberg, A. Br. J. Hæmat. 1969, 17, 257. 8. Fielding, J. J. clin. Path. 1965, 18, 88. 9. Wapnick, A. A., Lynch, S. R., Charlton, R. W., Seftel, H. C., Bothwell, T. H. Br. J. Hæmat. 1969, 17, 563. 10. O’Brien, R. T. Ann. N.Y. Acad Sci. 1974, 232, 221. 11. Modell, C. B., Beck, J. ibid. p. 201. 12. Baficerzak, S. P., Westerman, M. P., Heinle, E. W., Taylor, F H. Ann. intern. Med. 1968, 68, 518. 13. Kaye, S. B., Owen, M. Br. med. J. 1978, i, 342. 14. Kaye, S. B., Owen, M. Q. Jl Med. (in the press). 6. 7.
480
view
was
sified,
a
that, if only the
really
effective
could be intenwould have been
treatment
approach
found.
pursuing these thoughts, PROPPER and his colleagues in Boston hit upon the idea of infusing the drug subcutaneously from small portable syringe pumps over 12 hours of each day.1.1S They were able to show that a given amount of drug is far more effective when administered by this route, that much more drug can be given daily, that the In
excellent response is maintained at least over 1 year, that the apparatus can be managed by the patients at home in the long term, and that some patients prefer subcutaneous infusion to intramuscular injections.. Now PIPPARD, CALLENDER, and WEATHERALL3 report that all the patients they have studied, including 5-year-olds, can be put into impressive negative iron balance. With 4 g of desferrioxamine infused subcutaneously daily, excretion of from 1 to 4 mg Fe per kg per day can be induced. 2 g produces half the response, but even this compares favourably with venesection for hasmochromatosis, in which removal of 1 unit of blood per week unloads 0-5 mg Fe per kg per day from an adult. It suggests that the iron load in transfusiondependent children could be stabilised between 3 and 4 years of age, at about 4 g. Though there has not been time to show a statistically convincing improvement in organ function in older patients, these findings have raised hopes among patients and doctors alike that an effective treatment for transfusional iron overload is available at last. How should the clinician now proceed? As so often, decisions about treatment have to be made on incomplete evidence. What is more, parents of affected children are alert to new forms of treatment, and they will be pressing hard for subcutaneous infusion. But the price of the drug at 3-12 ($6) per g is sufficient to cause anxiety even in Britain, and is simply too much for some other communities. The annual cost of 2 g desferrioxamine per day for all existing patients in Britain (300) would be nearly £3/4 million; in Cyprus (500) £1¼ million; in Greece (2000)16 nearly ,5 million, and in Italy (12 000)" ,28 million; owing to new births these costs would double in 10 years. Progress in treatment will cause much bitterness, and many families in the Middle East and the Far East will beggar themselves in attempting to obtain adequate treatment for their child. It is therefore of pressing importance to establish the minimum effective dose of desferrioxamine given subcutaneously, to support the development of cheaper iron-chelating drugs, and to explore alternative 15.
R. D., Nathan, D. G., Cooper, B., Rufo, R. R., Nienhuis, A. W., Anderson, W. F. Blood, 1976, 48, 964.
Propper,
16. Loukopoulos, D. in Iron Bergsma, A. Cerami, C. 1977. 17. Rotoli, B. ibid.
Metabolism and Thalassæmia (edited by D. M. Peterson, and J. H. Graziano). New York,
to these diseases. Fortunately, prevention of thalasssemia is now possible by antenatal diagnosis,18-20 and there is a big demand for this service in Mediterranean countries. This timely de-
approaches
may help to spare at least some comwhich munities might otherwise have to choose whether to undertake an open-ended and crippling commitment to an ever-expanding group of patients, or to refuse treatment to patients with one of the commonest childhood diseases.
velopment
Graft-versus-host Reactions and Autoimmune Disease ACCORDING to a widely accepted model, human beings and other mammals are in a state equivalent to low-dose tolerance of their own body constituents : clones of T lymphocytes with specific receptors for autoantigens are eliminated or suppressed, whereas B lymphocytes with surface immunoglobulins having high affinity for autoantigens prevail. When helper activity is provided by T lymphocytes specifically stimulated by viral or other antigenic determinants, or non-specifically stimulated by
adjuvants
or
graft-versus-host (G.V.H.) reactions,
these B lymphocytes proliferate, differentiate, and form autoantibodies. Non-specific and specific lymphocyte stimulation (for example G.v.H. reactions and virus infections) might have synergistic effects in the production of autoimmune disease. A prediction of this model, that G. v. H. reactions would result in the formation of autoantibodies and autoimmune diseases, has been amply confirmed in animals. For example, repeated injections of parental lymphocytes into Fl mice induced the formation of antinuclear antibodies, and allotype markers established that these were formed by host rather than donor lymphocytes.2 The induction of
Coombs-positive
autoimmune haemolytic antmias undergoing G.V.H. reactions has been anasome detail. 3,4 The antibodies eluted from the erythrocytes of affected animals were found to be of recipient allotype, polyclonal, and reactive with erythrocytes of several mouse strains. Hamsters with G.V.H. reactions are likewise prone to severe autoimmune haemolytic anæmia.5 Mice with G.V.H. reactions also tend to get glomerulonephriin mice lysed in
18. Kan, Y. W., Golbus, M. S., Trecartin, R., Furbetta, M., Cao, A. Lancet, 1975, ii, 790. 19. Alter, B. P., Modell, B., Fairweather, D., Hobbins, J. G., Mahoney, M. J., Frigoletto, F. D., Sherman, A. S., Nathan, D. G. New Engl. J. Med. 1976,
295, 1437. Fairweather, D. V. I., Modell, B., Berdoukas, V., Alter, Blanche P., Nathan, D. G., Loukopoulos, D., Wood, W., Clegg, J. B., Weatherall, D. J. Br. med. J. 1978, i, 350. 1. Allison, A. C. Lancet, 1971, ii, 1401; Allison, A. C. in Immunological Tolerance (edited by D. H. Katz and B. Benacerraf); p. 25. New York, 1974. 2. Fialkow, P. J., Gilchrist, C., Allison, A. C. Clin. exp. Immun. 1973, 13, 479. 3. Lindholm, L., Rydberg, L., Strannegård, O. Eur. J. Immun. 1973, 3, 511. 4. Gleichmann, E., Gleichmann, H., Wilke, W. W. Transplant. Rev. 1972, 13,
20.
156. 5. Streilein, J. W., Stone, M. J., Duncan, W. R.
J. Immun. 1975, 114, 255.
Mediterranean, the Middle East, and the Far East, but now that treatment with regular blood-transfusions is becoming common in many of these areas, transfusional iron overload has been promoted to an important cause of death among adolescents. Desferrioxamine remains the only widely available drug for treating transfusional iron overload. Unfortunately it is expensive, being a complex hyd-
THE LANCET
Desferrioxamine and Transfusional Iron Overload CHRONIC subcutaneous infusion of the iron-che-
lating drug desferrioxamine, an imaginative new approach to the control of transfusional iron-overload,’-3 confronts the clinician with difficult scientific and ethical decisions. Transfusional iron overload is the consequence of regular blood-transfusion for refractory anaemia. Children with thalassaemia major are by far the largest group of such patients, though a sizeable second group is made up of children with erythrogenesis imperfecta, aplastic anaemia, and severe sickle-cell disease, and of adults with, for instance, sideroblastic anxmia and myelofibrosis. A transfusion-dependent patient usually receives an average of 0.3 mg of iron per kilogram per day intravenously as blood-i.e., from 3 mg daily in a 10 kg child to 21 mg daily in a 70 kg man. There is no significant excretion of iron. The natural history of iron overload among children with thalassxmia major is now well understood.4 There are no clinical signs until the age of 11 years, but then growth usually slows owing to endocrine disturbances; subsequently failure of puberty is common, and cirrhosis, hypoparathyroidism, and diabetes may follow : patients die of refractory cardiac failure, usually heralded by arrhythmias, at age 16-22. Thus, iron does not cause serious symptoms until the body iron load has risen to more than 20 g (the equivalent of 100 units of blood), and death occurs at a load of about 60 g (the equivalent of 300 units). There may also be a time factor-in other words, a smaller iron load over a longer period may produce similar complications, so an accumulated iron load of more than 10 g is cause for anxiety. The natural history of adult transfusional haemosiderosis is less well described, but the above figures fit well with the pathological data of BUJA and ROBERTS5 showing that serious iron loading in the heart starts at a transfusional load of 100 units. Thalassxmia major used to be one of the major causes of infant mortality in some parts of the 1.
Propper, R. D., Shurin,
S. B., Nathan, D. G. New
Engl. J.
Med. 1976,
294,
1421. 2.
roxylamine produced by
a
Streptomyces
grown in
culture. The colourless drug is injected parenterally ; it combines with iron, probably in the liver parenchymal cells,6 and the rust-coloured iron complex is excreted, about two-thirds in the urine and one-third in the stool.’ Most investigators have measured only the urinary component of the iron excretion. The response to the drug is related, with wide individual variations, to the body iron load88 and is enhanced by ascorbic acid given orally.9,10 A standard intramuscular injection of 500 mg of desferrioxamine removes less than 1 mg of iron from a normal adult or a 1-year-old child with thalassaemia, but in response to the same dose the average 8-year-old with thalasssemia excretes 8 mg of iron in the urine, which is the equivalent of the amount he receives each day as blood. The average 13-yearold excretes 17 mg, which is substantially more than his average daily intake as blood .4, 11 The response is maintained if the drug is given daily, so that the 8-year-old can be brought into iron balance and the 13-year-old into negative balance by intramuscular injection of a weight-related dose of 0.5-1.5g per day. However, the iron load at which balance seems to be achieved is about 15 g, as opposed to the normal stores of 1 g, and if such a large load remains toxic the treatment will achieve very little. Happily, intramuscular desferrioxamine does seem to protect the liver,12 and also the heart,l3,a from the damaging effects of iron. Desferrioxamine has now been used as chronic treatment for over 10 years with few unwanted effects; very rarely, it causes reversible cataracts. Thus, the results with intramuscular desferrioxamine are encouraging but necessarily incomplete, because, owing to the slow evolution of the condition, information about the drug’s effect on long-term survival cannot be obtained for many years. Even so, 2 years ago many clinicians felt that the evidence was already strong enough to warrant regular intramuscular desferrioxamine in all transfusion-dependent patients, and the general vat
Hussain, M. A. M., Flynn, D. M., Green, N., Hussein, S., Hoffbrand, A. V. Lancet, 1976, ii, 1278. 3. Pippard, M. J., Callender, S. T., Weatherall, D. J. Clin. Sci. mol. Med. 1978, 54, 99. 4. Modell, B. Archs Dis. Child. 1977, 52, 489. 5 Buja, L. M., Roberts, W. C. Am. J. Med. 1971, 51, 209.
Hershko, C., Cook, J. D., Finch, C. A. J. Lab. clin. Med. 1973, 81, 876. Cumming, R. L. C., Millar, J. A., Smith, J. A., Goldberg, A. Br. J. Hæmat. 1969, 17, 257. 8. Fielding, J. J. clin. Path. 1965, 18, 88. 9. Wapnick, A. A., Lynch, S. R., Charlton, R. W., Seftel, H. C., Bothwell, T. H. Br. J. Hæmat. 1969, 17, 563. 10. O’Brien, R. T. Ann. N.Y. Acad Sci. 1974, 232, 221. 11. Modell, C. B., Beck, J. ibid. p. 201. 12. Baficerzak, S. P., Westerman, M. P., Heinle, E. W., Taylor, F H. Ann. intern. Med. 1968, 68, 518. 13. Kaye, S. B., Owen, M. Br. med. J. 1978, i, 342. 14. Kaye, S. B., Owen, M. Q. Jl Med. (in the press). 6. 7.
480
view
was
sified,
a
that, if only the
really
effective
could be intenwould have been
treatment
approach
found.
pursuing these thoughts, PROPPER and his colleagues in Boston hit upon the idea of infusing the drug subcutaneously from small portable syringe pumps over 12 hours of each day.1.1S They were able to show that a given amount of drug is far more effective when administered by this route, that much more drug can be given daily, that the In
excellent response is maintained at least over 1 year, that the apparatus can be managed by the patients at home in the long term, and that some patients prefer subcutaneous infusion to intramuscular injections.. Now PIPPARD, CALLENDER, and WEATHERALL3 report that all the patients they have studied, including 5-year-olds, can be put into impressive negative iron balance. With 4 g of desferrioxamine infused subcutaneously daily, excretion of from 1 to 4 mg Fe per kg per day can be induced. 2 g produces half the response, but even this compares favourably with venesection for hasmochromatosis, in which removal of 1 unit of blood per week unloads 0-5 mg Fe per kg per day from an adult. It suggests that the iron load in transfusiondependent children could be stabilised between 3 and 4 years of age, at about 4 g. Though there has not been time to show a statistically convincing improvement in organ function in older patients, these findings have raised hopes among patients and doctors alike that an effective treatment for transfusional iron overload is available at last. How should the clinician now proceed? As so often, decisions about treatment have to be made on incomplete evidence. What is more, parents of affected children are alert to new forms of treatment, and they will be pressing hard for subcutaneous infusion. But the price of the drug at 3-12 ($6) per g is sufficient to cause anxiety even in Britain, and is simply too much for some other communities. The annual cost of 2 g desferrioxamine per day for all existing patients in Britain (300) would be nearly £3/4 million; in Cyprus (500) £1¼ million; in Greece (2000)16 nearly ,5 million, and in Italy (12 000)" ,28 million; owing to new births these costs would double in 10 years. Progress in treatment will cause much bitterness, and many families in the Middle East and the Far East will beggar themselves in attempting to obtain adequate treatment for their child. It is therefore of pressing importance to establish the minimum effective dose of desferrioxamine given subcutaneously, to support the development of cheaper iron-chelating drugs, and to explore alternative 15.
R. D., Nathan, D. G., Cooper, B., Rufo, R. R., Nienhuis, A. W., Anderson, W. F. Blood, 1976, 48, 964.
Propper,
16. Loukopoulos, D. in Iron Bergsma, A. Cerami, C. 1977. 17. Rotoli, B. ibid.
Metabolism and Thalassæmia (edited by D. M. Peterson, and J. H. Graziano). New York,
to these diseases. Fortunately, prevention of thalasssemia is now possible by antenatal diagnosis,18-20 and there is a big demand for this service in Mediterranean countries. This timely de-
approaches
may help to spare at least some comwhich munities might otherwise have to choose whether to undertake an open-ended and crippling commitment to an ever-expanding group of patients, or to refuse treatment to patients with one of the commonest childhood diseases.
velopment
Graft-versus-host Reactions and Autoimmune Disease ACCORDING to a widely accepted model, human beings and other mammals are in a state equivalent to low-dose tolerance of their own body constituents : clones of T lymphocytes with specific receptors for autoantigens are eliminated or suppressed, whereas B lymphocytes with surface immunoglobulins having high affinity for autoantigens prevail. When helper activity is provided by T lymphocytes specifically stimulated by viral or other antigenic determinants, or non-specifically stimulated by
adjuvants
or
graft-versus-host (G.V.H.) reactions,
these B lymphocytes proliferate, differentiate, and form autoantibodies. Non-specific and specific lymphocyte stimulation (for example G.v.H. reactions and virus infections) might have synergistic effects in the production of autoimmune disease. A prediction of this model, that G. v. H. reactions would result in the formation of autoantibodies and autoimmune diseases, has been amply confirmed in animals. For example, repeated injections of parental lymphocytes into Fl mice induced the formation of antinuclear antibodies, and allotype markers established that these were formed by host rather than donor lymphocytes.2 The induction of
Coombs-positive
autoimmune haemolytic antmias undergoing G.V.H. reactions has been anasome detail. 3,4 The antibodies eluted from the erythrocytes of affected animals were found to be of recipient allotype, polyclonal, and reactive with erythrocytes of several mouse strains. Hamsters with G.V.H. reactions are likewise prone to severe autoimmune haemolytic anæmia.5 Mice with G.V.H. reactions also tend to get glomerulonephriin mice lysed in
18. Kan, Y. W., Golbus, M. S., Trecartin, R., Furbetta, M., Cao, A. Lancet, 1975, ii, 790. 19. Alter, B. P., Modell, B., Fairweather, D., Hobbins, J. G., Mahoney, M. J., Frigoletto, F. D., Sherman, A. S., Nathan, D. G. New Engl. J. Med. 1976,
295, 1437. Fairweather, D. V. I., Modell, B., Berdoukas, V., Alter, Blanche P., Nathan, D. G., Loukopoulos, D., Wood, W., Clegg, J. B., Weatherall, D. J. Br. med. J. 1978, i, 350. 1. Allison, A. C. Lancet, 1971, ii, 1401; Allison, A. C. in Immunological Tolerance (edited by D. H. Katz and B. Benacerraf); p. 25. New York, 1974. 2. Fialkow, P. J., Gilchrist, C., Allison, A. C. Clin. exp. Immun. 1973, 13, 479. 3. Lindholm, L., Rydberg, L., Strannegård, O. Eur. J. Immun. 1973, 3, 511. 4. Gleichmann, E., Gleichmann, H., Wilke, W. W. Transplant. Rev. 1972, 13,
20.
156. 5. Streilein, J. W., Stone, M. J., Duncan, W. R.
J. Immun. 1975, 114, 255.
