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Zinc Status Relates to Hematological Deficits in Middle-Aged Women

Department of Pediatrics (S.N., A.H., I.M.), Kumamoto University, School of Medicine, JAPAN
Kikuchi Yojoen Health Care Center, (K.I.), JAPAN
Ashikita Institution for Disabilities in Development (T.M.), JAPAN

Address reprint requests to: Soroku Nishiyama, MD, Department of Pediatrics, Kumamoto University, School of Medicine, Honjo 1-1-1, Kumamoto, 860, JAPAN

	ABSTRACT

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Objective: The objective of our study was to investigate zinc (Zn) status and the effects of Zn supplementation in relation to iron deficiency anemia in middle-aged women. It is important to define the role of Zn in hematologic abnormalities and to determine the frequency of Zn deficiency.

Methods: Fifty-two Japanese women, selected from a health examination survey on 6200 women, had hemoglobin concentrations below 12.0 g/dl, total iron binding capacity (TIBC) below 390 µg/dl and fairly normocytemia. These 52 were divided into three groups and we then compared the hematological status before and after iron (group A) or Zn (group B) or iron plus Zn (group C) supplementation.

Results: After treatment, concentrations of hemoglobin (Hb) increased slightly in groups A and B, but not statistically significant. In group C, Hb levels were significantly increased from 10.8±1.1 to 12.8±1.1 g/dl. Furthermore, numbers of RBC and reticulocytes, and concentrations of albumin were also increased significantly. Increased values over 1.0 g/dl of hemoglobin levels were noted in four women (26.6%) in group A, three women (14.2%) in group B and 13 women (81.2%) in group C.

Conclusion: Zn status to some extent can account for hematological abnormalities in middle-aged women. At least 5.0% of middle-aged Japanese women may have Zn deficiency. Normocytic anemia with low TIBC levels may serve as a good indicator of a marginal Zn deficiency.

Key words: women, anemia, zinc deficiency, iron deficiency

Abbreviations: RBC=red blood cells • TIBC=total iron binding capacity • MCV=mean corpuscular volume • MCH=mean corpuscular hemoglobin

	INTRODUCTION

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Zinc (Zn) deficiency associated with iron deficiency anemia was apparently first recorded by Prasad et al in 1961 [1]. Such patients had a specific Zn deficiency consisting of dwarfism, hypogonadism, visceromegaly, and hematologic abnormalities that simulated iron deficiency anemia. However, the precise role of Zn in hematologic abnormalities in humans is not well understood.

We reported zinc deficiency in relation to anemia in women endurance runners based on total body zinc clearance [2]. We also reported that Zn supplementation aids in overcoming anemia in these endurance runners, in disabled patients and in premature infants [2,3]. This hematological picture simulates iron deficiency anemia. However, a low number of red blood cells (RBC) and low levels of total iron binding capacity (TIBC) did not differ from findings in a typical iron deficiency anemia, most revealed a normocytic normochromic anemia.

In most prior studies, Zn levels in plasma and hair have been measured [4,5]. However, the former parameter is not so useful to estimate the marginal or inadequate status of Zn nutrition [6], and the latter has seasonal variations in the rate of hair growth [6,7]. Compared to these parameters, measurements of leukocyte Zn content [8], thymulin and thymidinkinase concentrations in serum [9,10], body Zn clearance [11–13], clearance studies using a stable isotope of Zn [14] or low TIBC with normocytic anemia [2,3] are more reliable. The present study examined hematological events when iron and/or Zn was given in middle aged women with low levels of TIBC but with normocytic anemia.

	MATERIALS AND METHODS

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Materials
Patients studied were those included in a health examination survey in a rural society in Japan. Among 6200 women aged 35 to 60 years, 682 women (11.0%) had a hemoglobin concentration under 12.0 g/dl, of whom 328 women (48.1%) had serum TIBC concentrations under 390 µg/dl. Fifty-two of these 328 women were selected to receive treatment in this study. Five women had microcytemia [mean corpuscular volume (MCV) <79 fl], 45 showed normocytemia (MCV 80–100 fl), and two demonstrated macrocytemia (MCV >101 fl), respectively. With regard to hemoglobin, eight had hypochromic anemia [mean corpuscular hemoglobin (MCH) <27 pg] and 44 had normochromic anemia (MCH 28–34 pg). Forty subjects had RBC <390x10⁴/mm³, and 12 had RBC >391x10⁴/mm³. Age, body weight, height were 47.2±16.2 years, 53.5±4.7 kg and 156.2±3.2 cm, respectively. These 52 women had no evidence of chronic disease such as hepatitis, collagen and hematological diseases. Premenopausal and postmenopausal women numbered 24 and 48, respectively. Three women used tobacco, and five women drank alcohol.

These 52 women, divided randomly into three groups, were prescribed iron citrate 100 mg/day in group A (n=15), gluconate zinc 35 mg/day in group B (n=21), and iron citrate 100 mg plus gluconate zinc 35 mg in group C (n=16) for 6 weeks, respectively. Two 5-day dietary surveys were made by a registered dietitian prior to this treatment and during supplements of iron and/or zinc. Their daily diets contained adequate kcal (2230±223 kcal), protein (81±16 g), fat (70±18 g), carbohydrate (318±31 g) and copper (1.2±0.46 mg), except for calcium (560±186 mg), iron (8.8±1.2 mg) and Zn (7.6±1.8 mg). Thirty-six age-matched healthy women served as controls.

Methods
Serum concentrations were measured for albumin, phosphorous (Pi), iron, ferritin, TIBC, Zn, copper and erythropoetin. Informed consent was obtained from each subject, and the ethical committee of Kumamoto University gave permission for the study.

Zn and copper were measured by atomic absorption spectrophotometry (Perkin-Elmer model 403) [11], ferritin levels were measured using enzyme immunoassay kits and erythropoetin levels were measured using radio immunoassay kits (Chugai Institute, Tokyo, Japan). Intra-and-interassay coefficiency of variations were 4.9 and 6.8%, respectively. Albumin, phosphorous, TIBC and iron concentrations were measured using an autoanalyzer (Technicon Co, NY).

Statistics
A modified t-test (Student t-test) and a paired t-test were used for statistical assessments.

	RESULTS

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RBC, Hb and hematocrit (Ht) in controls were significantly higher than those in each of the treated groups. Serum Zn and copper concentrations did not differ in controls and therapy groups, although serum iron and ferritin levels in controls were significantly higher, and serum erythropoetin levels were significantly lower than those in each treated group (Tables 1 and 2). The subjects with microcytic hypochromic anemia had lower serum iron and ferritin levels than those in other subjects (data not shown). Before treatment, there were no differences in Hb, RBC, Ht, MCV, MCH and other biochemical and trace elements among the three treated groups, as shown in Tables 1 and 2. After treatment, concentrations of Hb increased slightly in groups A and B, albeit not statistically (Fig. 1). In group C (Zn plus iron therapy), Hb levels increased from 10.8±1.1 to 12.8±1.1 g/dl (p<0.01,Fig. 1). The numbers of RBC and reticulocytes, and concentrations of albumin were also increased (p<0.05). Values over 0.5 g/dl of Hb were seen in 10 women (66.6%) in group A, 11 women (52.4%) in group B and 16 women (100%) in group C, respectively. Values over 1.0 g/dl of Hb were seen in 4 women (26.6%) in group A, 3 (14.2%) in group B and 13 (81.2%) in group C.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Change in hemoglobin levels before and after treatment.

	DISCUSSION

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In some middle-aged women, although serum concentrations of Zn were fairly normal, the status of Zn was marginal. Similar observations were noted in diabetics, subjects with non-endocrinological short stature, physical immobilization, and endurance runners [2,11,12]. These marginal stage Zn deficiencies indicate low stores of total body Zn in liver, kidney and bone, as in previous reports [11–13]. Although symptoms of classical Zn deficiency such as acrodermatitis and delayed wound healing were not seen, these marginal cases do require Zn supplementation [2,11,15]. In those with sickle cell anemia, the patients with normal serum levels of Zn were in the marginal stage of Zn deficiency [16,17]. In the women we studied, their daily intakes of Zn (7.6±1.8 mg) and iron (8.8±1.2 mg) seemed to be lower than the recommended dietary allowances, Zn (12 mg/day in women) and iron (10 mg/day in women).

Zn deficiency was confirmed by stable isotopes in subjects with iron deficiency [18], which suggested that the avoidance of red meat increased the risk of iron and Zn deficiencies, and low serum ferritin concentrations suggested the possibility of low Zn nutrition. Similarly, our middle-aged women had a concomitant Zn and iron deficiency. There can be high and low levels in TIBC in subjects with iron deficiency anemia [19]. The absolute value for TIBC may be helpful in distinguishing between iron deficiency and the anemia seen in the presence of chronic disorders. However, there is a considerable deficiency in the bimodel distribution of TIBC values in some patients and TIBC may be decreased. When such patients are studied further, they were found to have a generalized hypoproteinemia, one indication of which is a decreased serum albumin concentration [20,21]. These low TIBC levels seen in subjects with iron deficiency anemia seemed to concur with normocytic anemia with low TIBC levels seen in our middle-aged women and leading Zn and iron deficiency. Although iron deficiency is accompanied by an increase in TIBC and RBC, and decrease in % saturation under usual circumstances, Zn deficiency can cause a decrease in TIBC and RBC, leading to an increased % saturation and normocytemia, even when iron deficiency is present. Thus, normocytic anemia with low TIBC levels might be good indicator for diagnosing Zn deficiency. To define Zn deficiency in such cases, it is important to rule out chronic diseases. After Zn therapy, TIBC levels increased, though not statistically significant.

Administration of ferrous citrate did not improve the anemia. In healthy persons with empty iron stores, a high absorption of iron usually leads to establishment of a positive iron balance [22]. A decrease in iron absorption, combined with increased elimination from the body, may explain the suboptimal iron status [22]. In addition, marginal Zn deficiency possibly contributes to the manifestation of anemia, as the combined administration of ferrous citrate and Zn increased the concentration of iron, RBC, Hb, and albumin levels. Studies concerning interactions between Zn and hematopoiesis were reported. Increased ⁶⁵Zn uptake by bone marrow of zinc-restricted rats suggested that a minimal amount of Zn is necessary to support expansion of erythrocytic compartment [23]. These experiments also suggested that metallotionein synthesis occurs in erythropoetin-sensitive precursor cells in bone marrow, in response to increased Zn accessibility. Metallotionein expression in rat bone marrow depends on dietary zinc but not cytokines such as interleukin-1 or interleukin-6 [24]. Intake of Zn alone may lead to adverse effects, because chronic Zn intake can lead to iron deficiency anemia [25].

Our study suggests that Zn plays a role in the hematopoiesis seen in middle-aged women, and at least 5.0% of middle-aged women might have Zn deficiency manifesting as normocytic anemia, as most of the 52 women in this study had improved their health status when ingesting Zn plus iron supplementation. Other parameters concerning body metabolism such as serum phosphorus and albumin which are decreased in Zn deficiency [2,15], and serum erythropoetin were all improved. Zn is clearly involved in several aspects of normal hematopoiesis by virtue of its role in many enzyme systems involved with DNA synthesis (including thymidine kinase and DNA polymerases) [26,27], and are key structural components of a large number of proteins. The binding of Zn stabilizes the folded conformations of domains so that they may facilitate interactions between the proteins and other macromolecules such as DNA [28]. Furthermore, the zinc-finger transcription factor, GATA-1, is required for erythropoiesis [29,30]. Thus, the administration of Zn in addition to iron presumably increases the production of proteins and globin relating to hematopoiesis in the bone marrow and the anemia is overcome.

	ACKNOWLEDGMENTS

 
We thank M. Ohara for critical comments.

Received June 1, 1997. Accepted November 1, 1997.

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