Disorders of Iron Metabolism

Sytnpositnn etnatologic Disorders Symposium on H Hematologic

Disorders of Iron Metabolism Nadeem Nimeh, M.D./:~ M.D.,':' and Ronald C. Bishop, M.D.~:~~:~ M.D.,:q,

Although present only in minute quantities in living organisms, iron has assumed a vital role in their growth and survival. This element is an integral constituent of the hemoglobin molecule and of enzymes responsible for the oxidative pathways. Recent developments in our understanding of the biochemistry and metabolism of iron have led to new insights into clinical disorders. This review will be devoted partly to the discussion of some basic aspects of iron metabolism. It will also deal with methods for the evaluation of iron stores. The final section of the review will discuss some clinical syndromes associated with deranged iron metabolism and their current treatment.

IRON METABOLISM The total amount of iron in a 70 kg man is approximately 4.5 gm, of which 2.6 gm (57 per cent) is present in hemoglobin and 0.4 gm (9 per cent) in myoglobin. 52 52 A small but vital fraction of the iron is present in mitochondrial cytochromes, catalase, and other cytochromes. A substantial portion (1.5 gm) is also present as non-heme storage iron in ferritin and hemosiderin.

Iron Absorption The usual diet contains 10 to 15 mg of iron per day, of which approximately 10 per cent is absorbed. Under normal circumstances there is a considerable degree of variation in the amount of iron absorbed. Part of this variation is related to the type of food ingested. Studies related to interaction of food iron and iron salts have identified two iron pools.57 pools.'" One is the heme he me iron pool made up of hemoglobin and myoglobin. The other is the non-heme iron pool. Absorption from the non-he me iron pool and heme iron pool is distinctly better than from the non-heme is not affected by ascorbic acid or vegetables. 5G 56 The non-heme iron pool, contained in vegetables, eggs, ferritin, and hemosiderin is weakly ab':'Fellow, Hematology-Oncology, Hematology-Oncology. University of Michigan, Michigan. Ann Arbor, Arbor. Michigan ';";'Professor, "":'Professor, Internal Medicine, University of Michigan, Ann Arbor, Michigan

No, 4, July 1980 Medical Clinics of North America - Vol. 64, No.

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sorbed, about 2 per cent compared to 22 per cent for heme iron. This 56 liver.06 absorption can be enhanced by ascorbic acid, meat, or liver. In the stomach the ingested iron is released from food by peptic digestion and is bound to high molecular weight chelators. These chelators and secreted hydrochloric acid probably stabilize the iron in a ss soluble form and prevent the formation of insoluble ferric complexes. 8s Iron then gets absorbed in the upper portion of the small intestine. It is believed that the regulation of iron absorption takes place at this level. There are many dietary constituents, such as phytates and phosphates, which are known to interfere with the process of absorption. Some gastrointestinal secretions, perhaps gastroferrin,88 and certain drugs interfere also. Other metals, namely cobalt and manganese, have been shown to compete with iron for absorption. I!, It. 87 Iron absorption is greatest high in the duodenum and decreases progressively along the gastrointes27 The amount of iron absorbed increases in a log-linear tract.27 tinal tract. '4 After relationship with the amount presented to the intestinal mucosa. 14 uptake by the mucosal cell, iron is either bound to an intracellular protein transferrin,42. 46,73 46, 73 which carries it rapidly across the mucosal resembling transferrin,42, cell to the plasma, or it is incorporated into ferritin in the epithelial cell. Regulation of Iron Absorption The major factor that regulates iron absorption under normal circumstances is the iron requirement of the body. It is known that, in subjects with iron deficiency, iron absorption from the intestine is increased, and in those with iron overload absorption is reduced. 77.64 , ()4 The precise mechanism of this regulation remains an intriguing question. Three major theories are currently proposed. In the first, the mucosal theory, it is assumed that the mucosa has an intrinsic mechanism for modifying the degree of absorption. This regulation is believed to depend on messenger iron from the plasma that gets incorporated into the epithelial cell which in turn will synthesize ferritin and prevent the absorption of unneeded iron, which eventually is shed into the gastroin64 The second theory postulates the presence of a hormonal testinal tract. tract.()4 '7 that acts on the mucosa and thus modulates absorption. Alfactor 17 though some hormones such as erythropoietin have been suggested for this role, no firm data are available to support this concept. The third theory is based on proposed functional differences between the two 20 iron-binding sites of plasma transferrin. 25 al."; Recently Cavill et al. 1() presented an interesting simplified formula for control of iron absorption. They suggested that serosal transfer is a reflection of an equilibrium between plasma iron and exchangeable iron in the tissues and that the absorption is proportional to Intestinal exchangeable pool T o tt a II exc hh angeabl bl e pooII T

. xX PIasma Iron turnover

They defined the exchangeable pool as the iron available for binding by circulating transferrin, without regard to the site or chemical form of the iron. This interesting concept may provide some explanation for the increased iron absorption in hemolytic states.

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Iron Transport Iron is transported in plasma bound to transferrin. This molecule is a single polypeptide chain with a molecular weight of 75,000 to 80,000 daltons. 62 , 82 It is distributed evenly between the plasma and the extravascular space. Transferrin readily circulates in the interstitial spaces and exchanges iron with all cells of the body. Under normal circumstances most of the transferrin iron is delivered to the developing erythrocytes. However, if transferrin is fully saturated, its iron goes to the liver 19 Transferrin does not deliver iron to the reticuloenparenchymal cells. 19 41 dothelial system. 41 After delivery from transferrin, iron is incorporated into an intra45 In spite cellular exchangeable pool of oflow low molecular weight complexes. 45 of its small size, this pool is of great functional importance in maintaining the equilibrium of various metabolic processes within the cell. This pool also is in equilibrium with the other organ pools, including the gastrointestinal mucosal transit pool, through transferrin iron, and probably plays a vital role in the regulation of iron absorption. Furthermore, this pool is believed to be the site of action of chelation therapy.,,3 py.53 The binding of transferrin to specific receptors on the reticulocyte during delivery of its iron, has been studied extensively.66 Evidence from electronmicroscopy and autoradiography with ferritin-labelled transferrin suggests that the transferrin molecule not only binds to the reticuloH7. BH cyte membrane but may actually enter the developing red blood cell. G7. 8G There is even a suggestion that the transferrin molecule carries this iron H8 directly to the mitochondria. G8 The precise mechanism of release of iron from transferrin is not 40 of clear. Iron is tightly bound to transferrin with a stability constant 40 1023M-l. I023M-l. This tight binding does not take place without the incorporation of an anion such as bicarbonate which seems to act as a bridging zone 40 It I t is very likely that the iron-releasing between the iron and transferrin. 40 mechanism involves an attack on this anion-binding site. site."2

Iron and the Reticuloendothelial System As the red blood cells become senescent, they are taken up by the reticuloendothelial system. Here the cell is broken down and the iron which was formerly present in hemoglobin is stored as trivalent iron (FellI) (Felll) in ferritin. When iron is to be released from ferritin, it must be 13 • 91 rH reduced to the divalent state (Fell). Agents such as ascorbic acid 13 probably act to enhance this reduction and may thus facilitate the release of iron from the ferritin molecule. Oxidizing agents then convert the iron to Felll for binding to transferrin. Ceruloplasmin may facilitate this oxidation reaction. 7171

EVALUATION OF IRON STORES Quantitative Phlebotomy The quantitative phlebotomy is one method for measuring iron stores.;;'5,32,70 32. 70 Blood may be removed from the subject subj ect at a rate of approxistores.

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mately 500 ml per week until the hematocrit falls to 40 and remains at this level. The amount of iron removed can be calculated on the basis of 0.5 mg iron per milliliter of blood or 250 mg of iron per 500 ml unit withdrawn, if the original hemoglobin concentration is in the range of 15 gm per 100 ml. This calculated amount approximates the amount of iron which had to be mobilized from storage depots to regenerate hemoglobin and, since the stores are now depleted, represents the storage iron prior to onset of the phlebotomies. Mean storage iron has been estimated as 47 It is 770 mg for males and 232 mg for females with this method. methodY obvious that this technique is not applicable to many of the clinical problems for which we would like to determine iron stores in individual patients. Iron Content of Biopsies Iron stores can be estimated by staining tissues with the Prussian Blue reaction. This is applicable especially to bone marrow preparations and liver biopsies. The preparations may be graded from 0 to 3, or on some other arbitrary scale. It should be apparent that this grading is rather subjective and concurrence by different examiners is not always obtained. It can be said that the presence of stainable iron in the reticuloendothelial cells of the marrow eliminates iron deficiency as a cause of anemia. Quantitative determination of iron concentration in liver or other biopsied tissue gives a better index of body iron stores. 99 The clinical situation should dictate whether or not it is used. Serum Iron and Transferrin Saturation The total iron binding capacity (TIBC) of serum (transferrin concentration), and the serum iron concentration can be used to calculate the valuable information per cent saturation of transferrin which provides valuabie when properly interpreted. The value of these determinations has been enhanced with the standardization recommended by the International Committee for Standardization in Hematology.43,44 These tests tend to reflect the iron stores. With increased iron stores, the transferrin saturation will be greater. Conversely, with iron deficiency, the serum iron concentration and the transferrin saturation will be low. The rate of erythropoiesis affects the plasma iron pool. With an increased rate of erythropoiesis, iron is removed more rapidly from the pool and the serum iron concentration is reduced. If erythropoiesis is slowed or stopped by a toxic influence such as chloramphenicol, an early manifestation is an increase in the serum iron concentration. Elevated serum iron and transferrin saturation are found in conditions such as aplastic anemia, acute leukemia, hemolytic anemia, ineffective erythropoiesis, and hemochromatosis. Transferrin synthesis takes place mainly in the liver and there are factors which influence the rate of synthesis and the resultant concentration in the plasma. An abnormally high TIBC is characteristic of iron pregnancy,36 deficiency. Increased TIBC is also seen in childhood, with pregnancY,36 3 ' Decreased TIBC is found in association and withestrogen with estrogen treatment. 37 10 malnutrition, GO with iron overload, cirrhosis of the liver, protein malnutrition/ and in numerous chronic inflammatory diseases.

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Chelatable Iron The normal man excretes less than 1.0 mg of iron in the urine in 24 hours. This can be increased slightly by the administration of certain chelating agents, notably deferoxamine. The exact nature of the chelatable iron is not clear, but that mobilized by deferoxamine is probably intracellular iron in transit from ferritin to some other functional form of 34.4:, iron. 34 . 45 The chelatable iron will depend on the amount of iron in the stores and can be estimated by several standardized methods 55 ., 6.6, 29 29 (Table 1).

Ferritin Assay Ferritin is made up of a complex spherical protein shell, apoferritin, which contains varying amounts of iron in its core as ferric hydroxidephosphate complexes. Apoferritin has a molecular weight of approxi30 and can hold up to 4,500 atoms of iron,31 mately 445,000 daltons 30 although it is not usually saturated. The iron in ferritin is the major form of storage iron in the body. Apoferritin is made up of 24 subunits of molecular weight 18,500 to 3o There are two types of subunits and the apoferritin in 19,000 daltons. 3o various tissues is made up of variable proportions of these subunit 75 Isoelectric focusing identifies numerous isoferritins and the types. 22 1.1, 75 21 The isoferritin profile will vary from tissue to tissue and among species. 21 78 10ading.78 profile of a given tissue may also vary with iron 10ading. co-workers'1 first showed, with radioimmunometric Addison and co-workers assay, that ferritin was present in measurable amounts in normal serum and that the concentration varied with body iron stores. The circulating 92 The origin of this ferritin ferritin is relatively unsaturated with iron. 33 ., 92 and its function is not known but it is heterogeneous and contains 92 . 61. 92 isoferritins characteristic of ferritin from liver and spleen. 33,61, Addison et aLl reported normal women to have serum ferritin concentrations of 10 to 56 ng per ml and normal men values of 12 to 128 ng per ml. Patients with iron deficiency had values below 12 ng per ml and in the case of excessive iron stores the values were greater than 1000 51 , 58 58 have supported these findng per ml (Table 2). Other investigators 5L ings and the serum ferritin concentration has become a valuable tool for the evaluation of iron stores and disorders of iron metabolism. It has been suggested that 1 JLg ferritin in the plasma is equivalent to f.Lg per liter of offerritin 8 mg of storage iron. 90 90 Table 1.

mg Deferoxamine Deferoxamine Test, 500 500 m9 In tram uscularly~:~ tramuscularly':' 24

HOUR URINARY

IRON EXCRETION (MC) (MG) (MEAN

DefiCiency Iron Deficiency Normal Iron Overload 29 al.'" ':'Adapted from Harker et al.

± ± S.D.)

0.1 ± 1.0 ± ± 12.7 ± ±

0.1 0.5 3.8

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Serum Ferritin Concentration MEAN ± ± SEM (p.,G (ILG PER LITER)

± 0.9 5.3 ±

Iron Deficiency Normal Male Female Iron Overload

52.0 ± 5.1 28.8 ± 3.3 1,528

RANGE RANGE

0.6-12 12-128 10-56 680-2.800 680-2,800

':'Adapted from Addison et aLl "Adapted al.'

There are situations in which the serum ferritin does not accurately reflect the iron stores. In inflammatory liver disease the serum ferritin 79 high.79 concentration is usually high. The mechanism for this is probably the 79 same as for elevation of the transaminase in liver disease. 79 Acute myeloblastic leukemia and acute lymphoblastic leukemia are associated with high serum ferritin concentrations which fall with a decrease in 72 blast count. count.72 Some other neoplasms such as Hodgkin's disease and 50. 63 <;:l carcinoma of the breast are also associated with elevated values. 50, There are attempts to correlate certain isoferritins with specific neoplasms. 44 It should be noted that there are immunologic differences among the various serum isoferritins, depending on their subunit composition. Such qualitative differences may interfere with accurate radioim83 munoassay of the serum ferritin. R8 This is most likely to occur if the elevated serum ferritin concentration is associated with a neoplastic dis22 order.22 order. IRON DEFICIENCY Iron deficiency in the adult man is almost always caused by bleeding. Dietary deficiency of iron and malabsorption of iron are seldom the primary causes of iron deficiency but may aggravate the problem or interfere with therapy. Women during the child-bearing years are in precarious iron balance and slight increases in menstrual losses can produce iron deficiency. A diet with an adequate amount of available iron will tend to forestall the development of deficiency. However, iron supplements in the form of ferrous sulfate may be necessary to correct a deficiency, if it develops. Iron supplements are also indicated during pregnancy, to prevent the development of iron deficiency. Growing children with their expanding blood volumes and demands for enzymes containing iron in all cells will also become iron deficient if adequate dietary iron is not supplied. Iron deficiency can perhaps best be defined in terms of depletion or absence of iron stores. This state can be demonstrated with a low serum ofless iron concentration, a transferrin saturation of less than 10 per cent, and 50 /-Lg per liter. liter.50 If necessary, a serum ferritin concentration below 12 JLg absence of stainable iron in marrow or liver may be used to support these

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findings. If negative iron balance in the adult or failure to meet growth requirements in the child continue after the storage iron is depleted, microcytic hypochromic anemia will develop. The therapy of iron deficiency is simple. Ferrous sulfate, V. S. P., D.S.P., given orally is still the most effective, rational and inexpensive treatment in most cases. It is advisable to start with 0.3 gm of ferrous sulfate (60 mg of elemental iron) once daily for two days, then twice daily for two days, and subsequently 0.3 gm three times daily, if it is tolerated. The dose of iron may be increased further, if desired, but the incidence of adverse symptoms can be expected to increase sharply if this is done. Iron is absorbed best with the patient in the fasting state, but the iron is poorly tolerated in this setting. Although foods (phosphates, phytates) will reduce the efficiency of iron absorption, the iron will be better tolerated if given with or immediately after meals. Intolerance of oral iron therapy, manifested by abdominal discomfort, constipation, or diarrhea, is largely a function of the amount of iron administered. If intolerance of iron develops, reduction in dose should be tried first. Although other forms of iron therapy may be better tolerated, it should be remembered that some of these preparations have lower doses of elemental iron. There is no documented advantage of combinations of iron with other metals, and delayed release preparations should be avoided since they bypass the site of best absorption (the upper duodenum). The patient should be observed for response to iron therapy. If anemia is present before treatment, the response will be manifested by an appreciable rise in red blood cell values in two weeks and a restoration of normal values in approximately 6 weeks. If there is no response or an inadequate response to iron therapy, the original diagnosis should be reviewed or complicating features such as continued blood loss or chronic inflammation should be sought. In order to replace iron stores, oral iron therapy should be continued for a minimum of 6 months after nor,nal. the red blood cell values have returned to nor,mal. The diagnosis of iron deficiency is not a complete diagnosis. The cause of the iron deficiency should be defined and corrected, if possible. In rare situations parenteral iron therapy is indicated for iron deficiency. These situations include malabsorption of iron and situations in which the iron therapy might aggravate a gastrointestinal abnormality such as ileitis or colitis. Another limited indication is the noncompliant or unreliable patient who may not cooperate with a program of oral iron therapy. Desired rapid response is not an indication for parenteral iron therapy. therapy. The erythropoietic response to oral iron therapy will approximate that of parenteral iron. The preparation of choice for parenteral iron therapy is iron dextran D.S.P. (Imferon). This contains 50 mg/ml of elemental iron. injection, V.S.P. Because of poor absorption of iron and staining of the skin when this preparation is given subcutaneously, it should be given deep intramuscularly with a technique that prevents its reflux to subcutaneous tissues. In adults, after a test dose of 0.5 ml has been given, iron dextran

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can be given in daily injections of2.0 to 5.0 ml (100 to 250 mg iron) until the calculated total dose of iron has been given. The dose of iron is based on the hemoglobin iron deficit with an additional 500 to 700 mg of iron added to replace the iron stores. For a 70 Kg person the iron dose can be estimated as follows: (15.0 gm/dl- Patient's Hgb Conc.) x 45 dl x 3.34 mg/gm + 70(}mg Total dose of iron in milligrams.

=

This figure should be divided by 50 mg per ml to obtain the dose in milliliters of iron dextran injection. Appropriate adjustments should be made for body size. It should be noted that suggested dosage according to body weight and hemoglobin concentration can be obtained from a table in the package insert which accompanies the product. Observation for response to parenteral iron therapy is essential. One course should be sufficient. This should not be repeated unless iron deficiency anemia recurs in a responsive patient. A preparation of iron dextran injection is also available without preservatives for intravenous use. This can be given by slow intravenous injection (0.5 ml per minute, 2.0 ml per injection). Some workers give larger amounts, or even the total calculated dose, diluted in 250 ml of saline, in one sitting. This latter method is not approved in the United States. Adverse reactions occur with parenteral iron and are more frequent with the intravenous route. These include fever, skin eruptions, back pain, hypotension and vascular collapse. Some of these reactions may be due to the introduction of free ionic iron.

THE ANEMIA OF CHRONIC DISORDERS The anemia of chronic disorders (ACD) should be considered in the differential diagnosis of iron deficiency anemia. The current concept of the pathogenesis of this type of anemia is that with chronic inflammation and certain other disorders the iron resulting from the catabolism of red blood cells is trapped in reticuloendothelial cells and not easily 15a described the available for hemoglobin synthesis. Cartwright and Lee 15a situation as sideropenic anemia with reticuloendothelial siderosis. In these chronic disorders, red blood cell survival is shorter than normal, and erythropoietin production in response to the anemia is less than 15a Typically, the serum iron concentration is low but the total expected. 15a binding capacity is also depressed. To make the diagnosis of anemia of chronic disorders, iron must be demonstrated in iron stores, either directly by marrow examination or by inference with the serum ferritin determination. The serum ferritin concentration has become a valuable diagnostic tool for this differential diagnosis. It should be normal or elevated (above 12 f.Lg f-Lg per liter) lit er) in anemia of chronic disorders and less than 12 f.Lg f-Lg per liter in iron deficiency. This anemia is usually not severe and treatment with iron is ineffective. The anemia usually resolves with improvement of the underlying chronic disorder.

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IRON OVERLOAD Increased iron stores are usually accompanied by a transferrin saturation greater than 50 per cent, a serum ferritin concentration above j.Lg per liter lit er and an increase in the chelatable iron. 53 , G,I;, 29 If definitive 300 J.tg answers are not obtained from these tests, marrow or liver specimens may be examined with the Prussian Blue technique. Conditions associated with increased iron stores include idiopathic hemochromatosis, refractory anemias requiring transfusions and chronic extravascular hemolytic states. The prototype for the discussion of the iron-loaded state is idiopathic hemochromatosis. This disease is inherited in an autosomal recessive mode and the controlling gene is on chromosome 6, closely linked to the lO , 85 R5 There is a high frequency ofHLA-A3 of HLA-A3 and HLA-B14 or HLA-A 10cus. locus. to. 55 85 HLA-B 7 antigens in these patients. 55, HLA-B7 • R5 Partial expression of the disease 1 ;; occurs in heterozygotes. 15 7 Powell and co-workers 7H () have shown that the ratio of the iron transported across the gastrointestinal mucosal cell to that which is taken up by the cell is greatly increased in hemochromatosis when compared to normal controls. They conclude from this that the defect in control of iron absorption is within the mucosal cell. It is possible that this defect in the mucosal cell could be conditioned by a factor elsewhere in the body. Although aberrations of plasma iron transport and changes in the handling of iron by the reticuloendothelial system have been postulated as mechanisms producing increased iron storage, no good supporting evidence is available. Slight increases in the absorption of iron from the diet over a span of years can explain the 25 gm of iron which the patient may have in stores when the diagnosis of hemochromatosis is made. The phenotypic expression of the disease is much more 24,• 84 R4 The affected female, with menstrual losses, is common in the male. 24 relatively protected from the accumulation of iron stores during the child-bearing period. Hemochromatosis is the result of excessive iron deposited as ferritin and hemosiderin throughout the body but particularly in liver, pancreas and myocardium. There is associated organ damage leading to cirrhosis, diabetes and cardiac arrhythmia or congestive heart failure. Slate gray skin pigmentation is the rule. In fully developed cases the serum iron concentration is elevated and the transferrin is saturated or nearly so. The increased iron stores are reflected by an elevated serum ferritin 28 , 49.79 The diagnosis j.Lg per liter. 28 concentration, usually above 1000 JLg should be verified with liver biopsy. This would be expected to show increased parenchymal iron and cirrhosis. The keystone to the treatment of idiopathic hemochromatosis is removal of excess iron. In those patients with normal erythropoiesis this can usually be accomplished with phlebotomies of 500 ml at weekly intervals until the hematocrit falls below 40. Eighty to 100 phlebotomies, equivalent to the removal of 20 to 25 gm of iron, may be done before the iron stores are depleted. Serial serum ferritin determinations will reflect 89 but are not necessary for monitoring. After Mter the state of the iron stores 89 the iron stores are depleted, the patient should be kept in that state with four to six phlebotomies annually.

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With the phlebotomy the skin pigmentation decreases, carbohydrate tolerance is at times improved, and serial liver biopsies, if performed, 20 liver.20 changes in will show removal of the iron from the liver. The cirrhotic cpanges 54.74 the liver have been reported to improve. 54. 74 Although there has been no well controlled, prospective clinical trial of phlebotomy therapy for idiopathic hemochromatosis, it is the opinion of most investigators that this is the treatment of choice, that patients show improvement with treatment, and that their life expectancy is increased with phlebotomy. 12 There is an 11 per cent incidence of hepatomas in patients with idiopath35 It ic hemochromatosis. 59 This has not been reduced with iron removal. 35 is hoped that early detection and vigorous treatment before the onset of cirrhosis will reduce the incidence of hepatomas. If the diagnosis of idiopathic hemochromatosis is made, it is important that the family members, especially siblings, be surveyed for evidence of iron overload. The serum ferritin concentration and transferrin saturation should be determined in these subjects. If both are normal, hemochromatosis is quite unlikely.77 If only one value is abnormal, the iron content of a liver biopsy should be determined. If increased iron stores are demonstrated, the subject should be treated as a patient with idiopathic hemochromatosis. Early diagnosis and treatment will prevent the further accumulation of iron in the storage depots and the resulting tissue damage. When iron overload occurs along with abnormal erythropoiesis (refractory anemia, aplastic anemia, sideroblastic anemia, sickle cell anemia, thalassemia, chronic extravascular hemolytic anemia) anemia),, phlebotomy therapy is not an option. This is true whether the excess iron is due to increased iron absorption, conditioned by increased erythropoiesis or due to transfused iron in the form of hemoglobin iron in red blood cells. In some of these cases, the iron overload will be comparable to that in idiopathic hemochromatosis and, if time permits, the consequences very similar. Iron excretion, which is extremely limited in the untreated patient, can be increased with chelation therapy. . (DTP A) Deferoxamine (DF) and diethylenetriamine pentaacetate (DTPA) have been the standards for chelation therapy over the past 15 years. Because of the required daily injections and the questionable effectiveness in producing negative iron balance in transfusion iron overload, these agents were not widely used. It remained for Barry et al.,8 Modell 65 and Constantoulakis et al. 18 to show that chelation therapy is and Beck 65 effective in controlling accumulation of iron and that progressive tissue 81 showed damage can be arrested with such a program. Propper et al. 81 that the iron excretion could be greatly increased with prolonged intravenous infusions of deferoxamine compared to the same dose given intramuscularly. It was also shown that prolonged subcutaneous infusions were about 84 per cent as effective as intravenous infusions with 3g .• 80 It is suggested that the prolonged contact of respect to iron excretion. 39 the chelating agent with the "labile" intracellular iron pool allows more 19 If 20 to 40 mg deferoxamine per Kg iron to be complexed and excreted. excreted.:39 Kg is given over an 8 to 16 hour period, up to 50 mg of iron may be excreted daily in the urine. The total iron excreted will depend on the amount in the total body storage pool.

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The prolonged subcutaneous administration of deferoxamine has become practical with the development of small portable infusion pumps. The medication can be programmed for an 8 to 16 hour period and the procedure interferes only slightly with sleep or daily activities. The patient or a family member can be trained to give the subcutaneous injections. Complications of this program have been limited almost completely to minimal reaction at the site of injection. It remains to be seen whether other adverse effects will come to light with longer or more widespread use. Ascorbic acid enhances urinary excretion of iron in most patients on therapy.8H This probably results from an increase in the "lachelation therapy.38 bile" pool of iron which is being mobilized from ferritin and made available for chelation. Ascorbic acid should be used cautiously, since it is possible that this adjunct may produce a toxic effect, especially on the myocardium.33, myocardium.33. (19 (;9 It is clear that negative iron balance can be produced with current chelation therapy and this is associated with an arrest of the organ changes associated with iron overload. It remains to be seen whether the health and the quality of life can be improved in these patients over a longer period and with wider usage. Most of the experience with this treatment has been in patients with thalassemia. It undoubtedly has application in patients with other refractory anemias requiring transfusions to maintain adequate hemoglobin values. Of course, in some of these patients the prognosis is such that iron overload is not a significant problem. Intuitively we think that early treatment with chelation and prevention of iron overload would be ideal. This concept will have to be tested with appropriately designed studies. The current challenge is to improve such treatment. New chelators 23.48 are being developed and evaluated. 23 ,48 Rhodotorulic acid can be prepared less expensively than deferoxamine and is twice as effective on a weight basis. 226(1 Dihydroxybenzoic acid is effective when given by 26 Perhaps a depot preparation of one 6f Of the parenterally adminismouth. 26 tered chelators can be developed. With further developments the chelation therapy may be made more effective and less expensive.

SUMMARY An attempt has been made to give an overview of current concepts of iron metabolism and some of its disorders. Although iron in minute amounts is necessary for the metabolism of most cells, it produces damage if present in excess. Most agree that excessive iron stores do not accumulate in the normal person because of control of iron absorption in the gastrointestinal mucosal cell. Storage iron may become excessive if this control is not present or if iron is given parenterally as with transfusions. Clinical tools for evaluation of iron stores include the serum iron concentration, the transferrin saturation, the deferoxamine test, Prussian Blue stains of liver and marrow and the serum ferritin concentra-

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tion. The serum ferritin concentration is an excellent screening test for iron deficiency or excessive iron stores. If the diagnosis of excessive iron stores is made, the iron should be removed with phlebotomies or with chelation therapy. With the demonstration of autosomal recessive inheritance of idiopathic hemochromatosis and the association of HLA markers with this abnormality the diagnosis should be made early in susceptible family members, and a phlebotomy program should be considered. With the newer techniques of chelation therapy, such as prolonged subcutaneous infusions of deferoxamine, iron overload as a complication of transfusion therapy can be avoided. The further development of new agents and new techniques for the administration of these agents should make chelation therapy even more effective and more acceptable in the future.

REFERENCES

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