ting cells such as bone marrow could sequester FH, from a metabolically active pool of folate coenzymes. Under such circumstances this could potentiate the metabolic consequences of inadequate folate intake or increase folate demands."
1. S. P. Rothenberg: A Macromolecular Factor in Some Leukemic Cells Which Binds Folic A c i d . Proc. SOC. Exp. Biol. Med. 133: 428432,1970
2. S. P. Rothenberg and M. Da Costa: Further Observations on the Folate-Binding Factor in some Leukemic Cells. J. Clin. Invest, 50: 719-726, 1971 3. M. Da Costa and S. P. Rothenberg: Appearance o f Folate Binder in Leukocytes and Serum o f Women Who are Pregnant or Taking Oral Contraceptives. J. Lab. Clin. Med. 83: 207-214, 1974. 4. M. Da Costa, S. P. Rothenberg, and B. Kamen: DNA Synthesis in Chronic Myelogenous Leukemic Cells: Comparison of Results in Cells Containing Folate Binding Factor to Replicating Cells without Binder. Blood 39: 621-627, 1972
THE CORRELATION OF SERUM FERRlTlN AND BODY IRON STORES The relationship between serum ferritin levels and total body iron stores is discussed. Recent work is evaluated which correlates these parameters in iron deficiency, liver disease, inflammation, renal failure, and states with increased red cell turnover. Key Words: serum ferritin, body iron stores, hepatocellular disease, chronic inflammation
The assessment of total body iron stores has long lacked an easy method of measurement. The differential desferrioxamine test,' where iron chelated and excreted is thought to be proportional t o body iron stores, requires a fair degree of cooperation from the subject studied and there is evidence that some of the iron chelated i s not derived from iron stores.* The most commonly used method i s assessment of the amount of iron present in the bone marrow but this is an uncomfortable procedure and a t best only semi-quantitative. Quantitative venesection t o the level of incipient iron deficiency and anemia is sensitive3 but impracticable. Certainly none of these methods i s suitable for large scale population surveys. In 1972, G. M. Addison and his colleagues published a sensitive radioimmunoassay for serum ferritin.4 Recently a 'two-
site' immunoassay has also been e ~ o l v e d . ~ In this modification, unlabeled antibody linked t o an immunoadsorbent couples with ferritin which then reacts with labeled antibody. Thus quantitation of label bound is a measure of ferritin concentration. It has become apparent that in many instances serum ferritin concentration is related t o the total body iron Ferritin is a high molecular weight compound composed of a protein shell of apoferritin synthesized by the liver surrounding a ferric hydroxide core, the whole forming an octahedral structure. It is the main storage form of iron in the liver and reticulo-endothelial system either as ferritin itself, or as hemosiderin which is thought t o be a complex aggregate of partially denatured ferritin. In contrast t o the iron stores (1 g in a normal adult male) the amount of ferritin found in the serum by radioimmunoassay is miniscule. The normal range for the two site assay i s generally NUTRITION REVIEWSIVOL. 33, NO. 1 I JANUARY 1975 11
accepted as 12 t o 300 ng per milliliter.5 In normal adults the known difference in iron stores between the sexes is reflected in the serum levels of ferritin. In one series of non-anemic individuals the geometric mean of serum ferritin levels was 140 ng per milliliter for males and 39 ng per milliliter for female^.^ Previous surveys found levels below 10 ng per milliliter in iron deficiency4 and supra-normal levels in states of iron overload.' Serum ferritin levels fall with repeated venesection* and in refractory anemias are proportional to the number of transfusions received.6 The main value of the immunoassay method is i t s ease, and i t s requirement of only small amounts of serum or plasma which make it eminently suitable for large scale surveys, e.g. of iron nutritional status in a population or the effect thereon of iron additives to food. However, it has also been claimed t o be of value in discriminating between true iron deficiency and the anemia complicating chronic infection or chronic inflammatory disorders. In both these situations the serum iron levels will be low and there is likely to be a microcytic hypochromic anemia. Some distinction between the two conditions may be found in the total iron-binding capacity which is usually raised in iron deficiency and low in the anemia of chronic disorders although there are exceptions. Assessment of bone marrow stores will usually provide the answer. There are, of course, therapeutic implications in assessing iron stores since the anemia of chronic d i ~ o r d e r ,even ~ if hypochromic and microcytic, will respond little to iron therapy. Since apoferritin is synthesized in the liver and ferritin is stored in large amounts therein, it seems probable that hepatic function could also affect the serum ferritin levels. A series of hospital patients has now been studied by D.A. Lipschitz and his co-workers" and the levels of serum ferritin correlated with other hematological parameters. Serum iron, total iron-binding capacity, and serum ferritin were measured in all subjects. Thirty-two patients with uncomplicated iron de12
NUTRITION REVIEWS/VOL. 33, NO. 1 /JANUARY 1975
ficiency were studied. The criteria for selection were a transferrin saturation of less than 16 percent ( 8 2 3 percent for the group), a total iron-binding capacity of greater than 400 ng per 100 mi (actually estimated as 479 ? 73 ng per 100 ml), and no evidence of an inflammatorv or hepatic disorder. In this group the mean serum territin was found to be 4 ng per milliliter with a range of 1 to 14 ng per milliliter. Conversely, in iron overloaded patients, high serum ferritin levels were found. In three patients with hemochromatosis untreated by venesection the values were 3215, 6018, and 6 1 0 0 ng per milliliter. In 20patients who had received a t least 20 blood transfusions the mean serum ferritin was 2713 ng per milliliter. A highly significant correla t i o n was observed between the number of transfusions and the serum ferritin level, and analysis of the data showed that each transfusion raised the serum ferritin by the order of 60 ng per milliliter. Thirty-nine patients were classified as having an inflammatory disorder on the grounds of clinical symptoms, erythrocyte sedimentation rate, pyrexia, or leucocytosis. Some of these patients were anemic with a mean hematocrit of 30 k 4 percent. Low serum iron levels were found, 38 k 11 p g per 100 ml, but total iron-binding capacity was low a t a mean of 227 k 81 p g per 100 ml. Transferrin saturation, therefore, was higher than that in iron deficiency a t 18 f 5 percent. In this group the mean serum ferritin was 305 ng per milliliter with a wide range of 10 to 1650 ng per milliliter. There was no apparent relation between serum ferritin and the duration, type, or severity of the inflammatory process. Thirty-seven patients had liver disease as assessed by increased serum bilirubin and high serum alkaline phosphatase levels. The majority had an alcoholic etiology and all these patients were anemic. The hematocrit of the group as a whole was 30 f 4 percent. This group had high serum iron levels, slightly reduced total iron-binding capacity, and high transferrin saturation. These patients had a high serum ferritin level with a mean of 509 ng per milliliter and a range
of 25 t o 3239 ng per milliliter. The mean values of the 29 patients with alcoholic liver disease were comparable with those of eight patients with viral hepatitis of whom only one was anemic. Nine additional patients had both liver dysfunction and evidence of an inflammatory process. Here the serum ferritin was higher still with a mean of 801 ng per milliliter and again with a wide range. Seventy-five of the patients in the inf Iam m a t o r y a n d hepatic dysfunction groups and a control group consisting of patients with other disorders had bonemarrow aspirations performed for the assessment of iron stores. These were categorized as absent, diminished, moderate, or increased and correlated with the basic diagnosis. Patients with inflammation showed elevation of the serum ferritin compared with the control group for a given amount of marrow iron. This was even more true of patients with liver disease. Thus, of those with absent iron stores, the 12 control patients had mean serum ferritin levels of 6 ng per milliliter, the patients with inflammation 21 ng per milliliter, and the patients with liver disease 61 ng per milliliter. A similar pattern of results was seen a t each level of bone marrow iron stores. Thus a low serum ferritin level provides evidence of iron deficiency, but the converse that a normal level excludes it, is not shown t o be so. Additionally an increased serum iron level may be due t o inflammation or hepatic disease, rather than to increased iron stores. In these two groups the few patients with additional iron deficiency did tend t o have lower serum ferritin levels than those without iron deficiency but the majority still fell within the normal range. Fifteen patients studied had an anemia with increased red cell turnover; seven patients with megaloblastic anemia, one with sideroblastic anemia, and eight with a hemolytic anemia. In this group the mean serum ferritin was high a t 419 ng per milliliter. Twelve of these patients had bone marrow aspirations. As with the previous groups, there was a tendency for serum ferritin levels t o be higher than normal for
a given quantity of bone marrow iron. For example, four patients with diminished iron stores had serum ferritin values of 61 t o 354 ng per milliliter. In nine patients with chronic renal disease who had not received iron therapy or blood transfusion, the mean serum ferritin was 32 ng per milliliter and levels showed a correlation with bone marrow iron stores comparable to the control group. A correlation was observed in these studies between serum ferritin and total iron-binding capacity but not with any other hematological parameter. This was particularly true for 39 patients with anemia and inflammation. The correlation is, of course, inverse with iron overloaded patients showing the highest serum ferritin and lowest total iron-binding capacity and iron deficiency showing converse results. This is an interesting observation and the authors suggest that total iron-binding capacity should receive more attention as a possible measure of total body iron stores. T h i s paper t h u s substantiates the hypothesis that serum ferritin will delineate uncomplicated iron deficiency. Iron deficiency compounded by hepatic disease or chronic inflammation wil I not necessariIy be manifest in the serum ferritin levels. Since a similar high ferritin was also found in hemolytic states, this presumably will also be the case in the uncommon situations where iron deficiency and hemolysis can co-exist, e.g. paroxysmal nocturnal hemoglobinuria. The conclusion suggested by this work is that in a patient with chronic inflammation a high serum ferritin will exclude iron deficiency but a result within the normal range will not. This aspect requires further investigation in a larger number of patients. It would also be of interest to investigate other anemias thought t o be due t o a block t o iron release b y t h e reticulo-endothelial cell, e.g. rheumatoid arthritis and neoplasias, particularly of the gut where there may be an associated iron deficiency due t o blood loss. The alcoholic patients with hepatic dysfunction included in this study were all NUTRITION REVIEWSIVOL. 33. NO. 1 I JANUARY 1975 13
anemic and it would be of interest t o have been given details of the etiology of the anemia. In this situation it is often a megaloblastic anemia due to a dietary deficiency o f folate or a secondary sideroblastic anemia. These are both conditions of increased red cell destruction and it might have been thought that some of the increase in serum ferritin levels could be attributable to this. However, although their number is small, the hepatitis patients of whom only one was anemic, showed comparable elevation of serum ferritin levels. Recent work’ where the ferritin and transferrin fractions of serum were sepa rated by ultracentrifugation after the a d m i n i s t r a t i o n of 59Fe-labeled heatdamaged red cells suggested that serum f e r r i t i n i r o n is largely derived from ret iculo-endothelial iron. Normally this i r o n comes from senescent red cells. Ferritin iron is then largely transported t o the hepatocytes. Transferrin, on the other hand, is concerned with transfer of iron from the liver and after absorption from the gut t o the developing erythropoietic cells. If these results are substantiated it seems notable a t first sight that in situations where the reticulo-endothelial system fails t o release iron, nevertheless, supranormal levels of ferritin, whose iron moiety is thought to be derived from this same source, are detectable in the plasma. However, more rapid turnover of apoferritin from damaged liver cells is likely in hepatocellular disease, but this is also a possibility in chronic inflammatory states where there are increases in other proteins synthesized in the liver, e.g. fibrinogen and haptoglobin. The development of methods for measuring ferritin have obviously opened up a new chapter in the field of iron metabolism and the next few years should see substantial advances. 0
14
NUTRITION REVIEWSIVOL. 33, NO. 1 I JANUARY 1975
1. J. Fielding, M. C. O’Shaughnessy, and G. M. Brunstrom: Differential Ferrioxamine Test in Idi opathi c Haemochromatosis and Transfusional Haemosiderosis. J. Clin. Path. 19: 159-164, 1966 2. K. S. Olsson: Iron Stores in Normal Men and Male Blood Donors. As Measured by Desferrioxamine and Quantitative Phlebotomy. Acta Med. Scandinav. 192: 401 -407, 1972 3. D. Haskins, A. R. Stevens, Jr., S. Finch, and C. A. Finch: Iron Metabolism. Iron Stores in Man As Measured by Phlebotomy. J. Clin. Invest. 3 1: 543-547, 1952 4. G. M. Addison, M. R. Beamish, C. N. Hales, M. Hodkins, A. Jacobs, and P. Llewellin: An lmmunoradiometric Assay for Ferritin in the Serum of Normal Subjects and Patients with fron Deficiency and Iron Overload. J. Clin. Path. 25: 326-329, 1972 5. L, E. M. Miles, D. A. Lipschitz, and C. P. Bieber: Anal. Biochem. in press 6. A. Jacobs, F. Miller, M. Worwood, M. R. Beamish, and C. A. Wardrop: Ferritin in the Serum of Normal Subjects and Patients with Iron Deficiency and Iron Overload. Brit. Med. J. 4: 206-211, 1972 7. M. A. Siimes, J. E. Addiego, and P. R. Dallman: Ferritin in Serum: Diagnosis of Iron Deficiency and Iron Overload in Infants and Children. Blood 43: 581-590, 1974 8. G. 0. Walters, F. M. Miller, and M. Worwood: Serum Ferritin Concentration and Iron Stores in N o r m a l Subjects. J. Clin. Path. 26: 770-772, 1973 9. G. E. Cartwright and G. R. Lee: The Anaemia of Chronic Disorders. Brit. J, Haematology 21: 147-152, 1971 10. D. A. Lipschitz, J. D. Cook, and C. A. Finch: A Clinical Evaluation of Serum Ferritin as an Index of Iron Stores. New Engl. J. Med. 290: 1213-1216, 1974 11. M. A. Siimes and P. R. Dallman: New Role for Serum Ferritin (SF) in Iron Metabolism. Pediat. Res. 8: 409, 1974
1. S. P. Rothenberg: A Macromolecular Factor in Some Leukemic Cells Which Binds Folic A c i d . Proc. SOC. Exp. Biol. Med. 133: 428432,1970
2. S. P. Rothenberg and M. Da Costa: Further Observations on the Folate-Binding Factor in some Leukemic Cells. J. Clin. Invest, 50: 719-726, 1971 3. M. Da Costa and S. P. Rothenberg: Appearance o f Folate Binder in Leukocytes and Serum o f Women Who are Pregnant or Taking Oral Contraceptives. J. Lab. Clin. Med. 83: 207-214, 1974. 4. M. Da Costa, S. P. Rothenberg, and B. Kamen: DNA Synthesis in Chronic Myelogenous Leukemic Cells: Comparison of Results in Cells Containing Folate Binding Factor to Replicating Cells without Binder. Blood 39: 621-627, 1972
THE CORRELATION OF SERUM FERRlTlN AND BODY IRON STORES The relationship between serum ferritin levels and total body iron stores is discussed. Recent work is evaluated which correlates these parameters in iron deficiency, liver disease, inflammation, renal failure, and states with increased red cell turnover. Key Words: serum ferritin, body iron stores, hepatocellular disease, chronic inflammation
The assessment of total body iron stores has long lacked an easy method of measurement. The differential desferrioxamine test,' where iron chelated and excreted is thought to be proportional t o body iron stores, requires a fair degree of cooperation from the subject studied and there is evidence that some of the iron chelated i s not derived from iron stores.* The most commonly used method i s assessment of the amount of iron present in the bone marrow but this is an uncomfortable procedure and a t best only semi-quantitative. Quantitative venesection t o the level of incipient iron deficiency and anemia is sensitive3 but impracticable. Certainly none of these methods i s suitable for large scale population surveys. In 1972, G. M. Addison and his colleagues published a sensitive radioimmunoassay for serum ferritin.4 Recently a 'two-
site' immunoassay has also been e ~ o l v e d . ~ In this modification, unlabeled antibody linked t o an immunoadsorbent couples with ferritin which then reacts with labeled antibody. Thus quantitation of label bound is a measure of ferritin concentration. It has become apparent that in many instances serum ferritin concentration is related t o the total body iron Ferritin is a high molecular weight compound composed of a protein shell of apoferritin synthesized by the liver surrounding a ferric hydroxide core, the whole forming an octahedral structure. It is the main storage form of iron in the liver and reticulo-endothelial system either as ferritin itself, or as hemosiderin which is thought t o be a complex aggregate of partially denatured ferritin. In contrast t o the iron stores (1 g in a normal adult male) the amount of ferritin found in the serum by radioimmunoassay is miniscule. The normal range for the two site assay i s generally NUTRITION REVIEWSIVOL. 33, NO. 1 I JANUARY 1975 11
accepted as 12 t o 300 ng per milliliter.5 In normal adults the known difference in iron stores between the sexes is reflected in the serum levels of ferritin. In one series of non-anemic individuals the geometric mean of serum ferritin levels was 140 ng per milliliter for males and 39 ng per milliliter for female^.^ Previous surveys found levels below 10 ng per milliliter in iron deficiency4 and supra-normal levels in states of iron overload.' Serum ferritin levels fall with repeated venesection* and in refractory anemias are proportional to the number of transfusions received.6 The main value of the immunoassay method is i t s ease, and i t s requirement of only small amounts of serum or plasma which make it eminently suitable for large scale surveys, e.g. of iron nutritional status in a population or the effect thereon of iron additives to food. However, it has also been claimed t o be of value in discriminating between true iron deficiency and the anemia complicating chronic infection or chronic inflammatory disorders. In both these situations the serum iron levels will be low and there is likely to be a microcytic hypochromic anemia. Some distinction between the two conditions may be found in the total iron-binding capacity which is usually raised in iron deficiency and low in the anemia of chronic disorders although there are exceptions. Assessment of bone marrow stores will usually provide the answer. There are, of course, therapeutic implications in assessing iron stores since the anemia of chronic d i ~ o r d e r ,even ~ if hypochromic and microcytic, will respond little to iron therapy. Since apoferritin is synthesized in the liver and ferritin is stored in large amounts therein, it seems probable that hepatic function could also affect the serum ferritin levels. A series of hospital patients has now been studied by D.A. Lipschitz and his co-workers" and the levels of serum ferritin correlated with other hematological parameters. Serum iron, total iron-binding capacity, and serum ferritin were measured in all subjects. Thirty-two patients with uncomplicated iron de12
NUTRITION REVIEWS/VOL. 33, NO. 1 /JANUARY 1975
ficiency were studied. The criteria for selection were a transferrin saturation of less than 16 percent ( 8 2 3 percent for the group), a total iron-binding capacity of greater than 400 ng per 100 mi (actually estimated as 479 ? 73 ng per 100 ml), and no evidence of an inflammatorv or hepatic disorder. In this group the mean serum territin was found to be 4 ng per milliliter with a range of 1 to 14 ng per milliliter. Conversely, in iron overloaded patients, high serum ferritin levels were found. In three patients with hemochromatosis untreated by venesection the values were 3215, 6018, and 6 1 0 0 ng per milliliter. In 20patients who had received a t least 20 blood transfusions the mean serum ferritin was 2713 ng per milliliter. A highly significant correla t i o n was observed between the number of transfusions and the serum ferritin level, and analysis of the data showed that each transfusion raised the serum ferritin by the order of 60 ng per milliliter. Thirty-nine patients were classified as having an inflammatory disorder on the grounds of clinical symptoms, erythrocyte sedimentation rate, pyrexia, or leucocytosis. Some of these patients were anemic with a mean hematocrit of 30 k 4 percent. Low serum iron levels were found, 38 k 11 p g per 100 ml, but total iron-binding capacity was low a t a mean of 227 k 81 p g per 100 ml. Transferrin saturation, therefore, was higher than that in iron deficiency a t 18 f 5 percent. In this group the mean serum ferritin was 305 ng per milliliter with a wide range of 10 to 1650 ng per milliliter. There was no apparent relation between serum ferritin and the duration, type, or severity of the inflammatory process. Thirty-seven patients had liver disease as assessed by increased serum bilirubin and high serum alkaline phosphatase levels. The majority had an alcoholic etiology and all these patients were anemic. The hematocrit of the group as a whole was 30 f 4 percent. This group had high serum iron levels, slightly reduced total iron-binding capacity, and high transferrin saturation. These patients had a high serum ferritin level with a mean of 509 ng per milliliter and a range
of 25 t o 3239 ng per milliliter. The mean values of the 29 patients with alcoholic liver disease were comparable with those of eight patients with viral hepatitis of whom only one was anemic. Nine additional patients had both liver dysfunction and evidence of an inflammatory process. Here the serum ferritin was higher still with a mean of 801 ng per milliliter and again with a wide range. Seventy-five of the patients in the inf Iam m a t o r y a n d hepatic dysfunction groups and a control group consisting of patients with other disorders had bonemarrow aspirations performed for the assessment of iron stores. These were categorized as absent, diminished, moderate, or increased and correlated with the basic diagnosis. Patients with inflammation showed elevation of the serum ferritin compared with the control group for a given amount of marrow iron. This was even more true of patients with liver disease. Thus, of those with absent iron stores, the 12 control patients had mean serum ferritin levels of 6 ng per milliliter, the patients with inflammation 21 ng per milliliter, and the patients with liver disease 61 ng per milliliter. A similar pattern of results was seen a t each level of bone marrow iron stores. Thus a low serum ferritin level provides evidence of iron deficiency, but the converse that a normal level excludes it, is not shown t o be so. Additionally an increased serum iron level may be due t o inflammation or hepatic disease, rather than to increased iron stores. In these two groups the few patients with additional iron deficiency did tend t o have lower serum ferritin levels than those without iron deficiency but the majority still fell within the normal range. Fifteen patients studied had an anemia with increased red cell turnover; seven patients with megaloblastic anemia, one with sideroblastic anemia, and eight with a hemolytic anemia. In this group the mean serum ferritin was high a t 419 ng per milliliter. Twelve of these patients had bone marrow aspirations. As with the previous groups, there was a tendency for serum ferritin levels t o be higher than normal for
a given quantity of bone marrow iron. For example, four patients with diminished iron stores had serum ferritin values of 61 t o 354 ng per milliliter. In nine patients with chronic renal disease who had not received iron therapy or blood transfusion, the mean serum ferritin was 32 ng per milliliter and levels showed a correlation with bone marrow iron stores comparable to the control group. A correlation was observed in these studies between serum ferritin and total iron-binding capacity but not with any other hematological parameter. This was particularly true for 39 patients with anemia and inflammation. The correlation is, of course, inverse with iron overloaded patients showing the highest serum ferritin and lowest total iron-binding capacity and iron deficiency showing converse results. This is an interesting observation and the authors suggest that total iron-binding capacity should receive more attention as a possible measure of total body iron stores. T h i s paper t h u s substantiates the hypothesis that serum ferritin will delineate uncomplicated iron deficiency. Iron deficiency compounded by hepatic disease or chronic inflammation wil I not necessariIy be manifest in the serum ferritin levels. Since a similar high ferritin was also found in hemolytic states, this presumably will also be the case in the uncommon situations where iron deficiency and hemolysis can co-exist, e.g. paroxysmal nocturnal hemoglobinuria. The conclusion suggested by this work is that in a patient with chronic inflammation a high serum ferritin will exclude iron deficiency but a result within the normal range will not. This aspect requires further investigation in a larger number of patients. It would also be of interest to investigate other anemias thought t o be due t o a block t o iron release b y t h e reticulo-endothelial cell, e.g. rheumatoid arthritis and neoplasias, particularly of the gut where there may be an associated iron deficiency due t o blood loss. The alcoholic patients with hepatic dysfunction included in this study were all NUTRITION REVIEWSIVOL. 33. NO. 1 I JANUARY 1975 13
anemic and it would be of interest t o have been given details of the etiology of the anemia. In this situation it is often a megaloblastic anemia due to a dietary deficiency o f folate or a secondary sideroblastic anemia. These are both conditions of increased red cell destruction and it might have been thought that some of the increase in serum ferritin levels could be attributable to this. However, although their number is small, the hepatitis patients of whom only one was anemic, showed comparable elevation of serum ferritin levels. Recent work’ where the ferritin and transferrin fractions of serum were sepa rated by ultracentrifugation after the a d m i n i s t r a t i o n of 59Fe-labeled heatdamaged red cells suggested that serum f e r r i t i n i r o n is largely derived from ret iculo-endothelial iron. Normally this i r o n comes from senescent red cells. Ferritin iron is then largely transported t o the hepatocytes. Transferrin, on the other hand, is concerned with transfer of iron from the liver and after absorption from the gut t o the developing erythropoietic cells. If these results are substantiated it seems notable a t first sight that in situations where the reticulo-endothelial system fails t o release iron, nevertheless, supranormal levels of ferritin, whose iron moiety is thought to be derived from this same source, are detectable in the plasma. However, more rapid turnover of apoferritin from damaged liver cells is likely in hepatocellular disease, but this is also a possibility in chronic inflammatory states where there are increases in other proteins synthesized in the liver, e.g. fibrinogen and haptoglobin. The development of methods for measuring ferritin have obviously opened up a new chapter in the field of iron metabolism and the next few years should see substantial advances. 0
14
NUTRITION REVIEWSIVOL. 33, NO. 1 I JANUARY 1975
1. J. Fielding, M. C. O’Shaughnessy, and G. M. Brunstrom: Differential Ferrioxamine Test in Idi opathi c Haemochromatosis and Transfusional Haemosiderosis. J. Clin. Path. 19: 159-164, 1966 2. K. S. Olsson: Iron Stores in Normal Men and Male Blood Donors. As Measured by Desferrioxamine and Quantitative Phlebotomy. Acta Med. Scandinav. 192: 401 -407, 1972 3. D. Haskins, A. R. Stevens, Jr., S. Finch, and C. A. Finch: Iron Metabolism. Iron Stores in Man As Measured by Phlebotomy. J. Clin. Invest. 3 1: 543-547, 1952 4. G. M. Addison, M. R. Beamish, C. N. Hales, M. Hodkins, A. Jacobs, and P. Llewellin: An lmmunoradiometric Assay for Ferritin in the Serum of Normal Subjects and Patients with fron Deficiency and Iron Overload. J. Clin. Path. 25: 326-329, 1972 5. L, E. M. Miles, D. A. Lipschitz, and C. P. Bieber: Anal. Biochem. in press 6. A. Jacobs, F. Miller, M. Worwood, M. R. Beamish, and C. A. Wardrop: Ferritin in the Serum of Normal Subjects and Patients with Iron Deficiency and Iron Overload. Brit. Med. J. 4: 206-211, 1972 7. M. A. Siimes, J. E. Addiego, and P. R. Dallman: Ferritin in Serum: Diagnosis of Iron Deficiency and Iron Overload in Infants and Children. Blood 43: 581-590, 1974 8. G. 0. Walters, F. M. Miller, and M. Worwood: Serum Ferritin Concentration and Iron Stores in N o r m a l Subjects. J. Clin. Path. 26: 770-772, 1973 9. G. E. Cartwright and G. R. Lee: The Anaemia of Chronic Disorders. Brit. J, Haematology 21: 147-152, 1971 10. D. A. Lipschitz, J. D. Cook, and C. A. Finch: A Clinical Evaluation of Serum Ferritin as an Index of Iron Stores. New Engl. J. Med. 290: 1213-1216, 1974 11. M. A. Siimes and P. R. Dallman: New Role for Serum Ferritin (SF) in Iron Metabolism. Pediat. Res. 8: 409, 1974
