1 Studies on serum ferritin concentration and bone marrow iron stores in the healthy aged Tetsuo Aoki Since immunoradiometric assay has made the quantification of serum ferritin (SF) concentration possible, the level of SF has proven to reflect the level of body iron stores in healthy adults accurately. However, there are still very few reports on SF concentration in the aged available. Therefore, this study was undertaken to determine the normal level of SF in the aged (over 60 yrs.) and the relation between SF concentration and bone marrow iron stores in the aged. After measuring the Hb, SI, TIBC, TS% and SF concentration of the 186 healthy aged subjects included in the study, they were then divided into two groups of the theoretically healthy aged and those with an iron deficiency. It could be inferred that only 37 out of the 186 subjects (19.9%) were theoretically healthy with SF concentration of 13 `129 ng/ml (geometric mean : 38 ng/ml) in males and 15 `120 ng/ml (geometric mean : 32 ng/ml) in females : i.e. these values were lower than those observed in control groups of healthy young adults whose level were : 13 `370 ng/ml (geometric mean : 72 ng/ml) in males and 12 `370 ng/ml (geometric mean : 35 ng/ml) in females. The incidence of latent iron deficiency was higher in the aged with 36.8% (7/19) in males and 61.5% (40/65) in females than in the healthy young adults in whom it was 4.0% (5/125) in males and 52.5% (113/215) in females. The possibility of latent iron deficiency in females was higher than that of males both in the groups of aged subjects and young adults respectively. Regarding the relation between SF concentration and bone marrow iron stores, all but one of the cases with SF levels under 12 ng/ml revealed sideroblast counts below 40%, (i.e. sideropenia). The results showed that SF levels well reflect the labile iron stores which were deduced by sideroblast counts in the bone marrow. However, there was no correlation between the SF concentration and the number of hemosiderin granules in the bone marrow in the group of the healthy aged without anemia. Key words : serum ferritin concentration, aged, latent iron deficiency, sideroblast counts, hemosiderin granules Present address : Division of Geriatrics, The First Department of Internal Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, 113 Japan
2 16 (16) Table 1 Estimation of the objectively healthy aged (1) Exception was made of any subject suffering from chronic disorders or presenting with marked pathological symptoms. (2) In accordance with the diagnostic standards of WHO, exception was made of any subject presenting with a systolic pressure exceeding 160mmHg and/or a diastolic pressure superior to 95 mmhg. (3) Exception was made of any subject whose chest X-ray, ECG or pulmonary function was abnormal. (4) Exception was made of any subject whose general blood test revealed a WBC count of less than 3,000/mm3 or exceeding 8,500/mm3 or a RBC count of less than 350 ~ 104/mm3, Hb under 12g/dl or a Ht inferior to 35%. (5) Exception was made of any subject whose urine test or stool examination showed a positive occult blood reaction. (6) Exception was made of any subject with an erythrocyte sedimentation rate exceeding 30 mm at 1 hour or a positive CRP test. (7) Exception was made of any subject whose general urine tests revealed proteinuria or glycosuria of(+) or more. (8) Exception was made of any subject with a markedly glucose intolerance. (9) Exception was made of any subject whose blood chemistry tests revealed any abnormal value in the GOT, GPT, LDH, CPK, Al-P, ƒá-gtp, Total Bilirubin,Indirect Bilirubin, Total Protein, Albumin, Na, K, Cl, BUN, Creatinine, Total Cholesterol or Triglyceride. Aged subjects satisfying all of the above-listed items (1) to (9) were considered to be objectively healthy.
3 ( 17) 17
4 18 (18) Table 2 Incidence of anemia in the subjectively healthy aged * Incidence of anemia in females significantly different from control (p<0.05) Table 3 Hematological values (Mean }SD and Ranges) in subjectively healthy aged and control subjects Comparative statistics: According to age a : p<0.001 According to sex b : p<0.05 b': p<0.01 b": p<0.001 * Geometric mean values
5 Fig. 1 Serum ferritin concentration (ng/ml) in 186 subjectively healthy aged subjects The dotted. lines represent the maximum and minimum serum ferritin concentrations in control subjects. The figures are the mean serum ferritin concentrations in subjectively healthy aged subjects. (M : male, F : female) Table 4 Incidence of latent iron deficiency in the objectively healthy aged
6 Table 5 Hematological values (Mean }SD and Ranges) in objectively healthy aged and control subjects Comparative statistics : * Geometric mean values According to age a : p<0.05, a' : p<0.01, a" : p<0.001 According to sex b : p<0.05, b' : p<0.01, b" : p<0.001 Fig. 2 A Relationship between serum ferritin concentration (ng/ml) and serum iron (ƒêg/100 ml) in 19 non-anemic objectively healthy aged males Regression : r=0.666 (p <0.01)
7 ( 21) 21 Fig. 2 B Relationship between serum ferritin concentration (ng/ml) and transferrin saturation (%) in 19 non-anemic objectively healthy aged males Regression : r=0.698 (p<0.01) Fig. 3 Serum ferritin concentration (ng/ml) in 84 non-anemic objectively healthy aged subjects The horizontal dotted lines represent the maximum and minimum serum ferritin concentrations in control subjects. The figures are the mean serum ferritin concentrations in nonanemic healthy aged subjects. (M : male, F : female)
8 Table 6 Incidence of latent iron deficiency (the indicators of latent iron deficiency are SI, TS% and SF concentration) in objectively healthy aged and control subjects Table 7Clinical evaluation of serum ferritin concentration in the theoretically healthy aged (Geometric mean values and ranges) Fig. 4Correlation between serum ferritin concentration (ng/ml) and grade of bone marrow hemosiderin granules in non-anemic objectively healthy aged subjects The horizontal dotted line represents the minimum serum ferritin concentration in control subjects. Grade of hemosiderin granules 0or1+:Absence or depletion of bone marrow iron stores. 1+or 2+ : Normal range marrow iron stores. ( : male, œ : female)
9 Fig. 5 Relationship between serum ferritin concentration (ng/ml) and sideroblast count (%) in non-anemic objectively healthy aged subjects The horizontal dotted line represents the minimum serum ferritin concentration in control subjects; the vertical dotted line represents the minimum sideroblast counts in control subjects. ( :male, œ:female) Fig. 6 Correlation between sideroblast count (%) and grade of bone marrow hemosiderin granules in non-anemic objectively healthy,aged subjects The horizontal dotted line represents the minimum sideroblast count in control subjects. Grade of hemosiderin granules : 0or1+ :Absence or depletion of marrow iron stores, 1+or2+ : Normal range marrow iron stores. ( : male, œ : female)
10 Table 8 Relationship between bone marrow iron stores and hematological values in 18 objectively healthy aged subjects * : Mean }SD ** : Geometric mean values
13 1) Addison, G.M., Beamish, M.R., Hales, C.N., Hodgkins, M., Jacobs, A., and Llewellin, P. : An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. J. Clin. Pathol., 25, 326 `329, ) Jacobs, A., Miller, F., Worwood, M., Beamish, M.R., and Wardrop, C.A. : Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br. Med. IV J., (5834), 206 `208, Miles, L.E.M., Lipschitz, Bieber, C.P., and 3) D.A., Cook, J.D.: Measurement of serum ferritin by a 2-site immunoradiometric assay. Anal. Biochem., 61, 209 `224, ) Cook, J.D., Finch, C.A., and Smith, N.J.: Evaluation the a population. of iron status of Blood, 449 `455, , Walters, G.O., Miller, F.M., 5) and Worwood, M.: Serum ferritin concentration and iron stores in normal subjects. J. Clin. Pathol., 26, 770 `772, 1973.
14 28 (28) and Goldberg, A.: Incidence of iron deficiency, with and without anemia, in woman in general practice. Br. J. Haematol., 13, 790 `796, ) Luxton, A.W., Walker, W.H.C., Gauldie, J., Ali, M.A.M., and Pelletier, C.: A radioimmunoassay for serum ferritin. Clin. Chem., 23, 683 `689, ) Loria, A., Hershko, C., and Konijn, A.M. : Serum ferritin in an elderly population. J. Gerontol., 34, 521 `524, ) Valberg, L.S., Sorbie, J., Ludwig, J., and Pelletier, O.: Serum ferritin and the iron status of Canadians. Can. Med. Assoc. J., 114, 417 `421, ) Custer, R.P., and Ahlfeldt, F.E. : Studies on the structure and function of bone marrow. II. Variation in cellularity in various bones with advancing years of life and their relative response to stimuli. J. Lab. Clin. Med., 11, 960 `962, ) Hartshock, R.J., Smith, E.B., and Petty, C.S. : Normal variations with ageing of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. Am. J. Clin. Pathol., 43, 326 ` ) Thomas, J.H., and Powell, D.E.B.: Causes of anemia."blood disorders in the elderly", p.7 `8, John Wright and Sons Ltd., Bristol, ) Jacobs, A., Owen, G.M. : The effect of age on iron absorption. J. Gerontol., 24, 95 `96, ) Freiman, H.D., Tauber, S.A., and Tulsky, E.G. : Iron absorption in the healthy aged. Geriatrics, 18, 716 `720, ) Gale, E., Torrance, J., and Bothwell, T.: The quantitative estimation of total iron stores in human bone marrow. J. Clin. Invest., 42, 1076 `1082, ) Trubowitz, S., Warren, L., Miller, L., and Zamora, J.C. : The quantitative estimation of non heme iron in human bone marrow aspirates. Am. J. Clin. Pathol., 54, 71 `77, ) Weinfeld, A.: Storage iron in man. Acta Med. Scan. (Suppl.), 421, 9 `155, available iron stores in man. J. Lab. Clin. Med., 33, 81 `86, ) Krause, J.R., and Stole, V. : Serum ferritin and bone marrow iron stores. II. Correlation with low serum iron and Fe/TIBC ratio less than 15%. Am. J. Clin. Pathol., 74, 461 `464, ) Kaplan, E., Zuelzer, W.W., and Mouriquand, C.: A study of stainable nonhemoglobin iron in marrow normoblasts. Blood, 9, 203 `213, ) Hansen, H.A., and Weinfeld, A. : Hemosiderin estimations and sideroblast counts in the differential diagnosis of iron deficiency and other anemias. Acta Med. Scand., 185, 333 `356, ) Kew, M.C., Torrance, J.D., Derman, D., Simon, M., Macnab, G.M., Charlton, R.W., and Bothwell, T.H. : Serum and tumour ferritins in primary liver cancer. Gut, 19, 294 `299, ) Marcus, D.M., and Zinberg, N. : Measurement of serum ferritin by radioimmunoassay; Results i normal individuals and patients with breast cancer. J. Nat. Cancer Inst., 55, 791 `795, ) Gropp, C., Havemann, K., and Lehmann, F.G. Carcinoembryonic antigen and ferritin in patients with lung cancer before and during therapy. Cancer, 42, 2802 `2808, ) Parry, D.H., Worwood, M., and Jacobs, A.: Serum ferritin in acute leukemia at presentation and during remission. Br. Med. J., I (5952), 245 ` 247, ) Jacobs, A., and Worwood, M. : Medical progress, ferritin in serum, clinical and biochemical implication. N. Eng. J. Med., 292, 951 `956, ) Leyland, M.J., Harris, H., and Brown, P.J. : Iron status in a general practice and its relationship to morbidity. Br. J. Nutr., 41, 291 `295, ) Ø ºˆè Y:Sideroblast ÉŠÖ éœ. æ ˆê ÒŒŒ tž¾š³ Æ Sideroblast. ªŽRˆã ïž, 69, 1773 `1798, ) Weinfeld, A. : Iron stores. "Iron deficiency", p. 329 `372, Academic Press, London, ) Batata, M., Spray, G.H., Bolton, F.G., Higgins, G., and Wollner, L. : Blood and bone marrow changes in elderly patients, with special reference to folic acid, vitamin B 12, iron, and ascorbic acid. Br. Med. J., II (5553), 667 `669, ) Rath, C.E., and Finch, C.A.: Sternal marrow hemosiderin, a method for the determination of