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Stem Cells, Vol. 15, No. 4, 291-296, July 1997
© 1997 AlphaMed Press

Serum Ferritin Iron, a New Test, Measures Human Body Iron Stores Unconfounded by Inflammation

Victor Herberta, Elizabeth Jayatillekea, Spencer Shawa, Alan S. Rosmana, Patricia Giardinab, Robert W. Gradyb, Barbara Bowmanc, Elaine W. Gunterc

a Departments of Medicine, Mount Sinai School of Medicine, New York, New York, USA and Bronx VA Medical Center, Bronx, New York, USA;
b Department of Pediatrics, New York Hospital-Cornell Medical Center, New York, New York, USA;
c Nutritional Biochemistry Branch, Centers for Disease Control, Atlanta, Georgia, USA

Key Words. Ferritin iron • Iron stores • Inflammation • Hemochromatosis • Iron overload

Dr. Victor Herbert, 130 West Kingsbridge Road, Bronx, NY 10468-3922, USA.


   Abstract
Top
 Abstract
Introduction
 Methods
 Human Sera
 Results
 Discussion
 References
 
Serum ferritin protein is an acute phase reactant. We hypothesized that serum ferritin protein generated in response to an inflammatory process would have much less iron (Fe) in it than would "normal" ferritin protein, and therefore measuring serum ferritin iron would assess human body iron status unconfounded by inflammation.

Basic Methods. We measured serum ferritin iron in 140 clinical samples obtained from the serum banks of Bronx VA Medical Center Hematology and Nutrition Laboratory (Bronx, NY), the CDC Nutritional Biochemistry serum sample bank (Atlanta, GA), and the sample bank from patients with thalassemia and iron overload treated at New York Hospital (New York, NY). Each was analyzed for three conventional criteria of iron status: serum iron, percentage of transferrin saturation and ferritin protein. In addition, tests for inflammation were also performed: C-reactive protein, WBC and transaminases. Seventy-seven patients' sera from 140 screened met each of three consistent criteria for stages of iron status.

Serum ferritin was immobilized by immunoprecipitation with rabbit antihuman polyclonal antibody bound to agarose and separated from other iron-containing proteins, digested with 0.2 ml of 3N nitric acid and analyzed for iron content by atomic absorption spectroscopy.

Results. Serum ferritin iron ranged in normal controls from 10 ng to 35 ng Fe/ml. The patients with iron deficiency (4/4) and those in negative iron balance (5/6) had values <=10 ng. Positive iron balance (8/9) and iron overload (22/22) values were >35 ng/ml, in contrast to 11/19 with inflammation. Seventeen of twenty-two with overload had values >100 ng/ml while only 1/19 with inflammation had such a value. Ferritin iron in ferritin protein was >15% by weight in 14/22 with iron overload but in 0/19 with inflammation.

Implications of the Work. Serum ferritin iron is a simple, direct measure of iron stores that we propose, in conjunction with measuring serum ferritin protein, as a minimally invasive screening procedure for accurately assessing the whole range of human body iron status, unconfounded by inflammation.


   Introduction
Top
 Abstract
 Introduction
Methods
 Human Sera
 Results
 Discussion
 References
 
Because serum ferritin protein is an acute phase reactant, rising with any inflammatory process from infection through chronic disease, to determine whether a high serum ferritin protein is due to iron (Fe) overload or inflammation, it has been necessary also to determine serum levels of Fe and percentage of saturation of serum iron binding capacity (transferrin). Transferrin is a reverse acute phase reactant. Thus, a high serum ferritin accompanied by a high percentage of saturation of a normal serum transferrin usually indicates iron overload; however, a high serum ferritin accompanied by a percentage saturation of transferrin <45 usually indicates that inflammation caused the high ferritin [1-5].

Body iron is stored within molecules of ferritin directly related to body iron stores of denatured ferritin (hemosiderin) and appears to be in equilibrium with them [6-9]. Ferritin protein is an iron-containing spherical rhombic dodecahedron protein of 24 repeating subunits with a molecular weight of approximately 460,000 [10], with an iron core of ferric-oxide phosphate and, when fully saturated, may be over 20% iron by weight. In states of iron overload or excess, the iron composition of ferritin increases [9, 11-15] and may contribute significantly to circulating non-transferrin iron [15]. In states of iron depletion, it decreases [7-9, 15, 16].

A small fraction of ferritin in equilibrium with stores circulates in the plasma; plasma ferritin protein is elevated in the presence of excess stores and is decreased with iron deficiency [7-11, 15]. Quantitated serum ferritin measured using antibody to ferritin protein does not reflect iron content of the ferritin. Serum ferritin protein is an acute phase reactant and apoferritin, (a ferritin protein with almost no iron in it, and not in equilibrium with body stores), is elevated in any inflammatory state, such as infection [17], rheumatoid arthritis [18], hepatitis [19], and cancer [20, 21] due in part to interleukin 1 enhancing the translation of apoferritin mRNA [22]. Therefore, transferrin-bound iron and transferrin saturation must be measured in the same serum sample with ferritin protein to distinguish iron status from inflammation. Just as a high serum ferritin protein may mean inflammation rather than iron overload, a low serum iron may mean inflammation rather than iron deficiency. Only if both serum iron and serum ferritin protein go in the same direction (i.e., both go up or down) can we reasonably assess iron status from them.

We hypothesized [1] that measurement of serum ferritin iron might accurately assess iron status and we developed this test to measure serum ferritin iron and examine it with respect to other serum tests of human iron status.


   Methods
Top
 Abstract
 Introduction
 Methods
Human Sera
 Results
 Discussion
 References
 
Four-Step Determination of Serum Ferritin Iron

Immunoprecipitation and Concentration of Ferritin   Rabbit antihuman ferritin polyclonal antibody (7 mg/ml) (Accurate Scientific; Westbury, NY) was diluted 0.1-10 ml with 0.2 M sodium bicarbonate at pH 8.2. Fifty {lambda} were mixed and incubated overnight at 4°C with 0.025 ml RepliGen IPA 400 Immobilized rProtein A cross-linked to agarose beads (RepliGen Corp.; Cambridge, MA) in a polypropylene tube. Antibody bound to agarose was stored at 4°C in individual tubes until used. For each serum sample to be assayed, immunoreactive ferritin was first determined. Sample aliquots were then selected (0.25-1 ml) so as not to exceed 90% of the capacity of the beads.

Excess antibody was removed from the beads by centrifugation and then 0.25-1 ml serum is added to each tube, incubated at room temperature with gentle rocking for two h, and allowed to stand overnight at 4°C.

Several methods of immunoprecipitation were compared including both polyclonal and monoclonal antibodies. Complete precipitation was verified by measurement of immunoreactive ferritin in an automated IMX system (Abbott Laboratories; Abbott Park, IL). The binding capacity (BC) of the coated beads varied with each batch from 310-395 ng ferritin protein/tube. Serum sample volumes were adjusted to insure complete precipitation (>99% of ferritin protein).

Washing to Remove Other Iron-Containing Proteins   The following morning, after spinning the tubes at 5,000 g, the serum was aspirated, the beads were washed twice with 2 ml aliquots of iron-free H2O, spun again at 5,000 g, the supernatant aspirated and the tubes dried overnight.

In several samples, verification of nonferritin iron removal was studied by using samples in which all immunoreactive ferritin was first removed with latex-coated beads containing rabbit monoclonal antihuman ferritin. The ferritin-free serum was then added to assay tubes and measurement of nonspecifically bound iron was conducted by the standard assay. Residual (nonferritin) iron following incubation and washing was minimal (3.4 ng ± 0.3 ng Fe).

Digestion   Each tube had 0.2 ml of HNO3 (3N) added which was vortexed and then heated for two h at 75°C in a waterbath (NB: probably 30-60 min is sufficient). All material was dissolved at this point.

Determination of Iron   Ten lambda aliquots of the nitric acid digest were assayed directly in an Atomic Absorption Spectrophotometer (Perkin Elmer Model 5000) with a graphite furnace (Model HGA 2200), under an argon atmosphere. Absorbance was measured at 248.3 nm. The sample was dried at 100°C for 50 sec (ramp time = 25 sec), charred at 1,500°C for 50 sec (ramp time = 20 sec) and atomized at 2,300°C for seven sec. Sensitivity of the assay was ~0.5 ng Fe. Determination of iron was verified by use of known standards, recovery experiments and colorimetric assay when feasible.

Immunoreactive ferritin was measured by rabbit antiferritin (monoclonal) bound to latex particles using an IMX system.


   Human Sera
Top
 Abstract
 Introduction
 Methods
 Human Sera
Results
 Discussion
 References
 
We tested 77 stored clinical serum samples which had three prior conventional tests for iron status defined by Bothwell et al. [20], modified by Herbert et al. [3] (serum iron, percentage of saturation of transferrin, serum ferritin protein [ Fig. 1]), and having an index of inflammation and clinical histories. The stages are: overload, positive balance, normal, negative balance, and deficiency. Samples were coded and analyzed in a "blind" fashion. The samples were obtained from excess serum collected for other clinical or research purposes in serum blood banks at the Hematology and Nutrition Research Laboratory, Bronx VA Medical Center, Bronx, NY; Department of Pediatrics, New York Hospital-Cornell, New York, NY (thalassemia samples); and the Nutritional Biochemistry Branch, Centers for Disease Control, Atlanta, GA. All samples had been stored frozen at -20°C for 1-8 months; those meeting only one or two of these three criteria were excluded. Inflammation was defined as the presence of any one of the following criteria: elevation of C-reactive protein (>1 ng/ml); peripheral blood WBC > 10,000 cells/mm3; >50% lymphocytes on differential; or transaminase elevations >2 x the upper limit of normal for respective clinical laboratories, plus a clinical history of hepatitis, nephritis or arthritis. Sixteen with iron overload due to thalassemia with ferritin protein >2,000 ng/ml were excluded because ferritin iron levels were uniformly extremely high (>200 ng/ml). Thirty-five met only one or two of three conventional criteria for iron status categorization. Twelve had conflicting criteria for staging iron status: eight had high ferritin levels (without evidence of inflammation) plus criteria of iron deficiency and four had low ferritin levels plus criteria of positive iron balance or iron overload.



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  		Figure 1. Serum ferritin iron at various stages of iron status. Each individual sample fulfilled all three usual criteria (appropriate serum iron, transferrin saturation, serum ferritin protein) for the stage of iron status. The frequency of values is shown in Table 1.

 
Included were four iron deficient, six iron depleted, and 17 normal iron status; nine positive iron balance; 22 iron overload, and 19 with inflammation. Among these 19, one also met iron overload criteria and two also met positive iron balance criteria ( Fig. 1).

We utilized disposable glassware, polystyrene and/or polypropylene tubes. All reagents, including HNO3, were of the lowest iron contamination available. Water and solutions were treated with Chelex 50-100 mesh (Sigma; St. Louis, MO).


   Results
Top
 Abstract
 Introduction
 Methods
 Human Sera
 Results
Discussion
 References
 
Determination of iron by atomic absorption spectroscopy was verified by known standards and recovery studies. Measurement of ferritin iron was linear from 0.2 ng to 2 ng/sample (r > 0.97); when it was greater than 2 ng, the curve became curvilinear. Dilutions contained <2 ng Fe injected per assay. Recovery studies were performed with known amounts of ferric chloride added to precipitated ferritins of known iron content just before digestion with nitric acid. Recoveries in 5 to 100 ng/ml serum were 95% ± 2.8%.

Values for ferritin iron for each group having differing iron status are shown in Figure 2. The cumulative frequency of serum ferritin iron values in different stages of iron status is shown in Table 1.



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  		Figure 2. The percentage iron by weight in 1 ml of serum ferritin in patients with iron overload and inflammation. A percentage composition >15% Fe by weight in 1 ml of ferritin protein was found in 14/22 patients with iron overload and 0/19 patients with inflammation. Not shown is that, among patients with positive iron balance, 4/9 were >15%, indicating iron overload.

 

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  		Table 1. Frequency of serum ferritin iron values among patients with different stages of iron status or inflammation
 
Among those with inflammation, one also meeting iron overload criteria had serum ferritin iron level equal to 85 ng/ml; two had positive balance criteria equaling 29 ng/ml and 16 ng/ml, respectively. The composition of ferritin (iron/protein) in iron overload and inflammation is shown in Figure 1.

Collectively, these data suggest that: A) serum ferritin iron levels <=10 ng/ml indicate a strong likelihood of iron deficiency (4/4) or negative iron balance (5/6) with only 2/17 "normals" having such values; B) values equal 10-35 ng/ml suggest normal iron status; C) values >35 ng/ml suggest positive iron balance (8/9), iron overload (22/22) or inflammation (10/19) (a percentage composition of ferritin >15% iron/protein excluded inflammation as the only cause of an elevated ferritin protein [inflammation 0/19, overload 17/22, positive balance 4/9]), and D) values >100 ng/ml suggest high probability of iron overload (17/22: positive balance 2/9, inflammation 1/19).

Measurement of serum ferritin iron alone (nl = 10-35 ng/ml) correctly diagnosed deficiency or depletion in 9/10 (with 2/17 false positive values), and positive balance or overload in 30/31 (with 1/9 false negatives). Among ferritin protein elevations due to inflammation, serum ferritin iron levels excluded 9/19; the remaining 10 were excluded by determining their ferritin protein was <15% iron by weight.

Sixty-three of 140 were excluded due to extremely elevated ferritin protein values or partial or conflicting conventional criteria for iron status. Of these 63, sixteen with thalassemia and long-term iron overload had extremely elevated ferritin levels (>2,000 ng/ml) and ferritin iron levels (>200 ng/ml). Forty-seven other patients did not meet all three criteria to be classified as one stage for iron status; 17 had only one or two criteria of iron depletion or deficiency. Each of the 17 had ferritin iron levels <35 ng/ml; of those with one or two criteria of either depletion or deficiency, 9/17 had serum ferritin iron levels <=10 ng/ml.

Eleven had either one or two criteria of positive iron balance: three had serum ferritin iron values >35 ng/ml, two were <=10 ng/ml, and the remaining eight were normal. Nine met either one or two conventional criteria of iron overload; seven had ferritin iron values >35 ng/ml. Four had two conventional criteria of iron overload but with low serum ferritin protein values (<=34 ng/ml); all four had ferritin iron values <=5 ng/ml. Eight had elevated ferritin protein levels >200 ng/ml, no evidence of inflammation, and one or two criteria of iron depletion or deficiency. Of those eight, five had normal range (10-35 ng/ml) ferritin iron values, one was low (<10 ng/ml) and two were elevated (>35 ng/ml). The latter two had ferritin iron of 43 and 75 ng/ml and ferritin protein values of 318 and 888 ng/ml, respectively. In both latter instances, percentage composition of ferritin iron/protein <15% by weight suggested that iron overload was not present.

The percentage of iron in ferritin in iron deficiency is falsely elevated due to the error of measuring adventitious iron at such low levels and so is not meaningful.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Human Sera
 Results
 Discussion
References
 
Our new method for measuring serum ferritin iron can distinguish elevated ferritin due to inflammation from that due to iron overload as well as patients with iron depletion and deficiency. A practical laboratory method to assess iron status in populations has long been a major clinical problem [6-9, 23]. Clinically, a decrease in body iron stores can be identified by a marked reduction in serum total ferritin concentration and/or by a decrease in stainable iron in the bone marrow. The former occurs only after late depletion ( Fig. 1), not when there is coincident inflammation or megaloblastic anemia [24]. Bone marrow examination is not only an impractical clinical test, but shows normal iron despite actual iron deficiency when megaloblastic anemia is present [24]. Commonly recommended criteria for iron deficiency in an individual with diagnosed anemia are repeat total ferritin <15 µg/l, Hb <12 g/dl and hematocrit <36. As early negative iron balance and storage depletion occurs well before these levels, these are either late indicators or insensitive. Furthermore, anemia also occurs in severe iron overload [24]. Unfortunately, no current conventional serum indicator of iron status is diagnostic for iron deficiency. Serum ferritin protein declines as iron stores decline except when elevated by inflammation because ferritin protein is an acute phase reactant. A decline to <15 µg ferritin protein/l occurs even in iron-supplemented women, and, contrarily, does not always occur in unsupplemented deficient women. Cook et al. [12] found prevalence of anemia among individuals with one abnormal serum index (low serum ferritin protein, low serum iron, low saturation of iron BC, or elevated erythrocyte protoporphyrin) was 11%, only slightly higher than 8% for the entire population. In contrast, anemia was present in 28% of individuals with two abnormal values, and in 63% of those with three. National Health and Nutrition Evaluation Survey II suggested, for survey purposes, two or three abnormal indicators of iron status were more indicative of iron deficiency or biological severity than a single indicator. The term "impaired iron status" was applied to abnormality in two or three tests. We found low serum ferritin iron was a useful single test of iron depletion or deficiency.

Similar difficulty presents for diagnosis of iron overload or excess. Measurement of serum ferritin protein levels is generally accepted as the best noninvasive means to determine body iron stores, but only if serum level of ferritin protein and serum level of iron run in the same direction. Elevations in serum ferritin protein levels may occur without elevation of iron stores in acute inflammatory conditions or in liver disease or cancer [15-21] where serum ferritin protein is usually >400 ng/ml. Serum ferritin protein levels >400 ng/ml define iron overload in most clinical laboratories, but, in fact, such interpretation requires confirmation by finding a high percentage of saturation with iron of iron BC (transferrin). In our study, serum ferritin iron clearly distinguished those with homozygous hemochromatosis from those with elevated ferritin due to inflammation; percentage of saturation of ferritin protein with iron uniformly separated those with high body iron from those with inflammation.

Our data suggest that a ferritin protein >150 ng/ml, when accompanied by a ferritin iron >35 ng/ml, means iron overload calling for therapy. We believe [3] that setting 400 ng/ml as the upper limit of "normal" ferritin protein is wrong, because it includes as "normal" those 12% of Americans with heterozygous hemochromatosis. Our data also suggest that a ferritin iron <35 ng/ml indicates no iron overload, even if the ferritin protein is >400 ng/ml.

Over 10% of Americans have an HLA-linked gene for iron overload, and up to 30% of Africans (and perhaps a similar percentage of African-Americans) have a non-HLA-linked gene for iron overload [6, 8, 14]. Thus, within the United States, there is a large population at risk not identifiable by HLA typing. In a recent study [14], a group of heterozygotes for hemochromatosis had significantly increased mean serum ferritin and mean transferrin saturation compared with controls with a wide range from the mean. Among these heterozygotes, hepatic iron is three- to fourfold higher than normals. Heterozygotes are at increased risk for heart disease [25-27], for adenomatous polyps of the colon [24] and several forms of cancer [28-30]. A large patient population study will be necessary to delineate whether measuring serum ferritin iron best identifies heterozygotes for iron overload.

This new assay for serum ferritin iron appears to not only discriminate every stage of iron status, but also does so in a more sensitive and specific manner than any of the older [31] serum tests for iron status ( Table 2).


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  		Table 2. Conventional tests of iron status compared with serum ferritin iron
 


   Acknowledgments
 
Supported in part by a grant from Quixote Associates, Inc. (V. Herbert, President).

Portions of this research have been previously published in abstract form [1-6].


   References
Top
 Abstract
 Introduction
 Methods
 Human Sera
 Results
 Discussion
 References
 

  1. Herbert V, Shaw S, Jayatilleke E et al. Most free-radical injury is iron-related: it is promoted by iron, hemin, holoferritin, and vitamin C, and inhibited by desferrioxamine and apoferritin. STEM CELLS 1994;12:289-303.[Abstract]

  2. Herbert V, Shaw S, Jayatilleke E. Method for measuring total body tissue iron stores. Patent #5,552,268, issued September 3, 1996, assigned to Quixote Associates, Inc.

  3. Herbert V, Shaw S, Jayatilleke E. Serum ferritin-iron (holoferritin): the first reliable (not confounded by inflammation) serum measure of body iron stores. J Invest Med 1995;43(suppl 1):198a.

  4. Herbert V, Shaw S, Jayatilleke E. Serum ferritin-iron (holoferritin): a new test for iron deficiency or excess. FASEB J 1995;9:A974.

  5. Herbert V, Shaw S, Jayatilleke E. High serum ferritin protein does not distinguish iron overload from inflammation, but a new assay, high serum ferritin-iron, does. Am J Clin Nutr 1995;61:89 and J Invest Med 1995; 43(suppl 2):242a.

  6. Herbert V, Shaw S, Jayatilleke E et al. Evidence of a new assay, % saturation of ferritin, is the most reproducible and reliable measure of the whole range of body iron stores. Blood 1995;86(suppl 1):584a.

  7. Alfrey CP. Serum ferritin assay. CRC Crit Rev Clin Lab Sci 1978:179-208.

  8. Herbert V. Everyone should be tested for iron disorders. J Am Diet Assoc 1992;92:1502-1509.[Medline]

  9. Cook JD, Finch CA. Assessing iron status of a population. Am J Clin Nutr 1979;32:2115-2119.[Abstract/Free Full Text]

  10. Worwood M, Dawkins S, Wagstaff M et al. The purification and properties of ferritin from human serum. Biochem J 1976;157:97-103.[Medline]

  11. Harris DC. Iron exchange between ferritin and transferrin in vitro. Biochemistry 1978;17:3071-3077.[Medline]

  12. Aungst CW. Ferritin in body fluids. J Lab Clin Med 1968;71:517-522.[Medline]

  13. Cook JD, Finch CA, Smith NJ. Evaluation of the iron status of a population. Blood 1976;48:449-458.[Abstract/Free Full Text]

  14. Adams PC. Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis. Am J Hematol 1994;45:146-149.[Medline]

  15. Lipschitz DA, Cook JD, Finch CA. Serum ferritin as a measure of iron stores. N Engl J Med 1974;290:1213-1216.

  16. Pootrakul P, Josephson B, Huebers HA et al. Quantitation of ferritin iron in plasma, an explanation for non-transferrin iron. Blood 1988;71:1120-1123.[Abstract/Free Full Text]

  17. Birgegard G, Hallgren R, Killander A et al. Serum ferritin during infection. Scand J Hematol 1978;21:333-340.[Medline]

  18. Rothwell RS, Davis P. Relationship between serum ferritin, anemia and disease activity in acute and chronic rheumatoid arthritis. Rheumatol Int 1981;1:65-67.[Medline]

  19. Reissman KR, Dietrich MR. On the presence of ferritin in the peripheral blood of patients with hepatocellular disease. J Clin Invest 1956;35:588-595.

  20. Matzner Y, Konijn AM, Hershko C. Serum ferritin in hematological malignancies. Am J Hemat 1980;9:13-18.[Medline]

  21. Jacobs A. Serum ferritin and malignant tumors. Med Oncol Tumor Pharmacother 1984;1:149-156.[Medline]

  22. Rogers JT. Genetic regulation of the iron transport and storage genes: links with the acute phase response. In: Lauffer RB, ed. Iron and Human Disease. Boca Raton, Florida: CRC Press, 1992:77-104.

  23. Bothwell TH, Charlton RW, Cook JD et al, eds. Iron Metabolism in Man. Oxford, England: Blackwell Scientific Publications, 1979.

  24. Herbert V. Introduction and medicolegal considerations. In: Herbert V, ed. Diagnosis and Treatment of Iron Disorders. Hosp Pract, 1991;16(suppl 3):4-6.

  25. Sempos CT, Looker AC, Gillum RF et al. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;330:1119-1124.[Abstract/Free Full Text]

  26. Balla G, Jacob HS, Balla J et al. Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 1992;267:18148-18153.[Abstract/Free Full Text]

  27. Sullivan JL. Stored iron as a risk factor for ischemic heart disease. In: Lauffer RB, ed. Iron and Human Disease. Boca Raton, Florida: CRC Press, 1992:295-312.

  28. Nelson RL, Davis FG, Sobin LH et al. Body iron stores and risk of colonic neoplasia. J Natl Cancer Inst 1994;86:455-460.[Abstract/Free Full Text]

  29. Stevens RG. Iron and cancer. In: Lauffer RB, ed. Iron and Human Disease. Boca Raton, Florida: CRC Press, 1992:333-347.

  30. Stevens RG, Jones Y, Micozzi MS et al. Body iron stores and the risk of cancer. N Engl J Med 1988;319:1047-1052.[Abstract]

  31. Worwood M. Laboratory determination of iron status. In: Brock JH, Halliday JW, Pippard MJ et al., eds. Iron Metabolism in Health and Disease. Philadelphia and London: WB Saunders Co, Ltd., 1994:449-476.

accepted for publication April 7, 1997.




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