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Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deficiency in infancy

Manuel Olivares, Tomás Walter, James D Cook, Eva Hertrampf and Fernando Pizarro

1 From the Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile, and the Division of Hematology, Department of Medicine, University of Kansas Medical Center, Kansas City.

2 Address reprint requests to M Olivares, Institute of Nutrition and Food Technology, Macul 5540, Casilla 138-11, Santiago 11, Chile. E-mail: molivare{at}uec.inta.uchile.cl.


ABSTRACT  
Background: The serum transferrin receptor (TfR) and the ratio of TfR to serum ferritin (TfR:SF) have been shown to be useful as early indicators of iron deficiency.

Objective: The objective of this study was to evaluate the performance of TfR and TfR:SF in the assessment of iron deficiency in infants and to analyze age-related changes in both variables.

Design: A total of 716 blood samples obtained from 515 healthy infants aged 8–15 mo were studied.

Results: In 144 samples in which all other laboratory indicators of iron status were within the reference range, the median and 95% CI for TfR and TfR:SF were 8.5 mg/L (95% CI: 5.9, 13.5) and 497 (95% CI: 134, 975), respectively. TfR and TfR:SF were significantly correlated with the other laboratory indicators of iron status. Furthermore, as the severity of iron deficiency progressed, there was a gradual increase in mean TfR concentration (P < 0.00001; analysis of variance). The sensitivity of TfR > 13.5 mg/L and TfR:SF > 975 in the diagnosis of iron deficiency was 23.6% and 68.4%, respectively. The specificity was 98.3% and 63.3% for TfR and TfR:SF, respectively. The sensitivity and specificity of SF < 10 µg/L were 63.7% and 60.8%, respectively. Receiver operator characteristic analysis showed that TfR and TfR:SF were more accurate than was SF alone in the diagnosis of iron deficiency.

Conclusions: TfR and TfR:SF showed age-related changes; TfR and TfR:SF appear to be better diagnostic tests for iron deficiency in infants than SF.

Key Words: Transferrin receptor • serum ferritin • ratio of transferrin receptor to ferritin • iron deficiency • infants


INTRODUCTION  
Iron deficiency continues to be one of the most prevalent nutritional deficiencies throughout the world. In the undeveloped world, infants are especially susceptible because of the high amounts of iron required for their growth coupled with a diet low in bioavailable iron.

The diagnosis of iron deficiency is based primarily on laboratory measurements. However, the tests used commonly have limitations due to their poor sensitivity or specificity, or because they are modified by conditions other than iron deficiency (1). The practice of using a battery of assays improves the precision of defining iron nutrition in a population (1); however, 2 pitfalls continue to confound this issue: the difficulty in accurately detecting mild iron deficiency and the identification of inflammation as a cause of changes in laboratory test results that are not due to iron deficiency. The serum transferrin receptor (TfR) assay has shown promise in the clarification of these pitfalls thus far because it is not influenced by acute or chronic inflammatory conditions (2, 3) and seems to be able to detect mild iron deficiency (4). However, its usefulness in the evaluation of iron status in infancy has not been fully evaluated.

In the diagnosis of iron deficiency, age-related variations in laboratory measurements must also be considered. Changes have been described for hemoglobin, mean corpuscular volume (MCV), serum iron, total-iron-binding capacity (TIBC), transferrin saturation (Sat), free erythrocyte protoporphyrin (FEP), and serum ferritin (SF) (1).

The determination of accurate reference values is pivotal to the adequate interpretation of population data and for the analysis of individual cases. Our aim was to assess whether TfR has developmental changes during infancy and to determine its usefulness in the diagnosis of iron deficiency during this period of the life cycle.


SUBJECTS AND METHODS  
Five hundred fifteen healthy, well-nourished infants aged 4–15 mo and of both sexes were studied. They were part of a cohort study designed to measure the effectiveness of an iron-fortified cereal in the prevention of iron deficiency anemia (5). The subjects belonged to a low- and low-middle-income group living in urban Santiago, Chile, and receiving their routine pediatric care in a Ministry of Health outpatient clinic. All the infants selected for the study weighed >3000 g at birth to ensure that neonatal iron stores were not compromised by premature delivery. Thus, any abnormalities in iron metabolism that were observed later in infancy would have been postnatal in origin. The infants were tested for iron status at ages 8, 12, and 15 mo. Infants with hemoglobin <105 g/L were excluded and treated. Thus, there were 1154 blood samples. We selected 716 samples for which there was sufficient serum, a full set of iron status measures, and a C-reactive protein (CRP) concentration <10 mg/L to avoid the possible effect of inflammation on iron metabolism indicators. Accordingly, some infants had several blood samples included in this analysis. No subject had shown any morbidity in the 2 wk before blood was drawn.

After informed, written consent was obtained from each infant's parents, a venous sample was drawn and the following iron nutrition status indexes were measured: red blood cell count (RBC), hemoglobin, and MCV (model ZBI; Coulter, Hialeah, FL); iron, TIBC, and Sat (6), FEP (Hematofluorometer; Helena, Beaumont, TX); SF (Ferrizyme; Abbott Diagnostics, North Chicago, IL); CRP (Turbox; Orion Diagnostica, Espoo, Finland); and TfR (by using a 2-site enzyme-linked immunoassay with monoclonal antibodies prepared against soluble transferrin-saturated receptor purified from human placenta; 7). TfR was measured after 4 mo of storage at –70°C. The receptor assay was standardized from the protein concentration of transferrin-free receptor isolated from human placenta. Six standards and all serum samples were analyzed in triplicate. The within-assay variability for a single measurement was 3–5%; the interassay variability was <3% (7). The ratio of TfR to SF (TfR:SF) was calculated by dividing TfR (in µg/L) by SF (in µg/L). The study was reviewed by and was in agreement with the standards set by the Institute of Nutrition and Food Technology's Ethics Committee on Human Research.

To evaluate the iron status of the infants, we used as the lower-normal limits for hemoglobin 110 g/L, for MCV 70 fL, for Sat 10%, and for SF 10 µg/L (1); we used an upper-normal limit for FEP of 2.12 µmol/L RBC at age 8 mo and 1.77 µmol/L RBC at age 12–15 mo (8). Iron status was considered to be normal when all of these laboratory indexes were within the reference range; depleted iron stores were defined as SF below normal, iron deficiency without anemia (ID) was defined as normal hemoglobin plus 2 abnormal laboratory results, and iron deficiency anemia (IDA) as hemoglobin below normal with 2 abnormal laboratory measurements.

Because SF concentration and TfR:SF have a skewed distribution, they were converted to logarithms before means and SDs were determined; the results were retransformed into antilogarithms to recover the original units and were expressed as geometric means and ±1 SD ranges. For the estimate of the medians and 95% CIs of TfR and TfR:SF, we used the calculation of percentiles that does not require the assumption of a normal distribution. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated to measure the performance of TfR, TfR:SF, and SF in the diagnosis of ID (9, 10). Sensitivity was defined as TP/(TP + FN) x 100 and specificity as TN/(TN + FP) x 100, where TP is true positive, FN is false negative, TN is true negative, and FP is false positive. The ROC curve is constructed by plotting the sensitivity on the ordinate as a function of the false positive rate (100 - specificity) for all possible cutoff values of the diagnostic test. The ROC curve is therefore applicable in cases in which the diagnostic test is distributed continuously. This method allowed us to perform multiple tests across a wide range of cutoffs and to decide the optimum cutoff according to the purpose of the test. The area under the ROC curve is the easiest measure of accuracy. This value varies between 0.1 and 1. An area of 0.5 represents the diagonal, attained when no discrimination exists. An area of 1 represents the perfect indicator.

Statistical analysis included analysis of variance (ANOVA), the one-sample Kolmogorov-Smirnov test, and Pearson's correlation. When the results of the ANOVA were significant, identification of significant differences between groups was based on Scheffe's post hoc test. Statistical analyses were performed with use of STATISTICA for WINDOWS (release 4.5; StatSoft Inc, Tulsa, OK).


RESULTS  
Of 716 blood samples studied, 20.1% indicated normal iron status, whereas 13.4%, 31.3%, and 12.8% indicated depleted stores, ID, and IDA, respectively. A single abnormal iron laboratory index other than SF was found in 22.4% of the infants. Mean (±SD) values for iron status indicators were RBC, 4.8 ± 0.3 x 1012/L; hemoglobin, 120 ± 9.8 g/L; MCV, 74.4 ± 4.4 fL; Sat, 12.6 ± 6.8%; and FEP, 2.12 ± 1.17 µmol/L RBC. Geometric means for SF and TfR:SF were 10 µg/L (range: 5–22) and 951 (range: 384–2356), respectively. The percentages of abnormal values were hemoglobin, 13.8%; MCV, 11.9%; Sat, 40.1%; FEP, 48.5%; and SF, 46.9%.

TfR, TfR:SF, and SF showed a significant correlation with the laboratory indicators of iron status (Table 1). The low r values observed were due mainly to a relatively flat regression curve throughout with relatively tight data.


View this table:
TABLE 1. Correlation of serum transferrin receptor (TfR) and the ratio of TfR to serum ferritin (TFR:SF) with laboratory indexes of iron status in the 716 infants1  
The median and 95% CI for TfR and TfR:SF in infants for whom all laboratory indicators of iron status were within the reference range are shown in Table 2. There were no age-related significant differences in either variable. Thus, the upper reference values for TfR and TfR:SF were set at 13.5 mg/L and 975, respectively.


View this table:
TABLE 2. Median (95% CI) of serum transferrin receptor (TfR) and ratio of TfR to serum ferritin (TfR:SF) in 144 iron-sufficient infants  
The cumulative probability plot of the natural logarithm of TfR:SF is shown in Figure 1. The log-transformed TfR:SF showed a normal distribution (Gaussian, one-sample Kolmogorov-Smirnov test; d = 0.03, NS) in the whole group of infants, including infants with iron sufficiency and with different stages of iron deficiency. There were no significant differences related to age in the distribution of log TfR:SF.


View larger version (20K):
FIGURE 1. . Cumulative probability of the natural logarithm of the ratio of serum transferrin receptor to serum ferritin in 716 infants aged 8–15 mo.

 
The effect of iron nutritional status on TfR concentration and TfR:SF is reported in Table 3. As the severity of the iron deficiency progressed, there was a gradual increase in mean TfR concentration (P < 0.00001, ANOVA). Infants with normal values had a significantly lower TfR:SF than did subjects with different stages of ID (P < 0.00001, ANOVA). TfR:SF was not significantly different among iron deficiency groups.


View this table:
TABLE 3. Serum transferrin receptor (TfR), ratio of TfR to serum ferritin (TfR:SF), and SF according to iron status1  
Anemic infants (hemoglobin < 110 g/L) had significantly higher TfR and TfR:SF values than did infants without anemia. The increase in these values was more pronounced in infants with a hemoglobin concentration <100 g/L than in those with a concentration 100 g/L (Table 4).


View this table:
TABLE 4. Serum transferrin receptor (TfR) and ratio of TfR to serum ferritin (TfR:SF) at different hemoglobin concentrations1  
There was an inverse relation between SF and TfR. TfR concentrations in subjects with SF concentrations of <5, 5–9, and >10 µg/L were 12.2 ± 4.3, 10.4 ± 3.0, and 9.6 ± 3.0 mg/L, respectively (P < 0.0001, ANOVA).

For the comparisons of the sensitivity, specificity, and ROC curves among TfR, TfR:SF, and SF, ID was defined as 2 abnormal iron status indicators (hemoglobin, MCV, Sat, and FEP), excluding SF. The sensitivity of TfR > 13.5 mg/L and TfR:SF > 975 in the diagnosis of ID was 23.6% and 68.4%, respectively. The specificity was 98.3% and 63.3% for TfR and TfR:SF, respectively. The sensitivity and specificity of SF < 10 µg/L were 63.7% and 60.8%, respectively. However, when SF was included as one of the indexes considered in the diagnosis of ID, the sensitivity and specificity of TfR > 13.5 mg/L were 17.7% and 75.3%, respectively.

To evaluate the usefulness of FEP alone, ID was defined as 2 abnormal iron status indicators (hemoglobin, MCV, and Sat), excluding FEP and SF. The sensitivity and specificity of FEP were 81.6% and 57.1%, respectively. With this change in the ID model, the sensitivity and specificity for TfR were 31.1% and 94.9% and for SF were 70.9% and 57.3%, respectively.

ROC curves for TfR, TfR:SF, and SF in detecting ID are shown in Figure 2. The areas under the ROC curves were 0.75 ± 0.02, 0.72 ± 0.02, and 0.67 ± 0.03 for TfR, TfR:SF, and SF, respectively. These curves show a higher accuracy of TfR and TfR:SF than of SF in the diagnosis of ID, with a similar performance of TfR:SF and TfR (TfR compared with SF, P < 0.01; TfR:SF compared with SF, P < 0.002; TfR compared with TfR:SF, NS).


View larger version (17K):
FIGURE 2. . Comparison of receiver operator characteristic curves for serum transferrin receptor (TfR), the ratio of TfR to serum ferritin (TfR:SF), and SF in detecting iron deficiency defined as 2 abnormal laboratory indexes of iron status (hemoglobin, mean corpuscular volume, transferrin saturation, and free erythrocyte protoporphyrin).

 

DISCUSSION  
A small amount of TfR circulates normally in plasma. It originates from the extracellular chain of TfR present in the membrane of every cell. The erythroid precursors in the bone marrow are the major determinants of these serum concentrations (11, 12). In conditions with increased erythroid marrow mass there is an elevation in TfR concentration, whereas in cases of erythroid hypoplasia or aplasia, serum TfR concentration falls (7, 11–13). The concentration of serum TfR also depends on the adequacy of iron availability to tissues (7, 11–14). When iron stores are exhausted and iron tissue availability is compromised, an early and progressive rise in serum TfR concentration occurs (4).

Our results corroborate the view that TfR is an indicator of iron status in infants. As the severity of the iron deficiency progresses, there is a gradual increase in mean TfR concentration. Furthermore, we observed that TfR correlates with other laboratory measures of iron status. The best correlation was found with MCV and FEP; a lower correlation was found with SF. These results were not surprising because SF is a measure of iron stores whereas TfR is a measure of tissue iron depletion, as are MCV and FEP. Kling et al (15) described a significant association of TfR with hemoglobin, FEP, iron, Sat, and SF (15). Virtanen et al (16) observed that TfR correlates with SF and MCV in infants. There was no correlation between TfR and other laboratory indicators of iron status. Yeung and Zlotkin (17) detected a lack of correlation of TfR with hemoglobin, FEP, and SF. In these 3 previous studies (15–17), most of the infants had iron-sufficient erythropoiesis, whereas in our study only 20.1% of the infants had a normal iron status. Moreover, the larger number of subjects in our study allowed a higher power in the statistical calculation of correlation.

In the infants studied, excluding those who were likely iron deficient, we found an upper reference value of 13.5 mg/L for TfR and of 975 for TfR:SF. These values are higher than those reported in adults when the same TfR assay measurement was used (4, 7). In adults, the upper reference values for TfR and TfR:SF are set at 8.5 mg/L and 500, respectively (4, 7). Other studies showed that infants had significantly higher values for TfR and TfR:SF than did adults (16–19). However, in one study, TfR values comparable with adult reference values were found in infants who were fed iron-fortified formula for the first 7 mo of life (15). The age-related changes in TfR could be explained by a higher erythropoietic activity per unit of body weight during infancy so that the relative contribution of red cell precursors to circulating TfR could be higher in this stage of the life cycle.

An increase in TfR concentrations was found in adults living at high altitudes, probably related to an increase in the total body erythroid mass (20). However, Virtanen et al (16) calculated that, even if the effect of growth is considered, the needs for new red blood cells/kg body wt is lower in infants than in adults. Because most infants classified as having normal iron status originated from the groups that had received formula or cereal fortified with iron, and because arbitrary cutoffs of iron status were used in our study to exclude subjects who possibly were iron deficient, it is unlikely that the higher TfR value observed in these infants was due to the presence of subjects with iron deficient erythropoiesis. It is known that that TfR increases just before or at the same time as SF decreases (4). Thus, another possibility is that some subjects with normal iron status may have been at the low end of the normal range, and these infants may have had rapidly declining, but still normal, SF, with compensatory increases in serum TfR. This would have significantly shifted the normal curve for TfR upward. When we attempted to exclude even very slight iron deficiency, we still found in 28 infants who met stricter cutoffs (hemoglobin = 115 g/L, MCV = 74 fL, Sat = 15%, FEP = 1.77 µmol/L RBC, and SF = 15 µg/L) that TfR was higher (upper 95% CI value: 12.8 mg/L) than in adults. Further research is needed to elucidate other physiologic mechanisms that could be involved in age-related changes in TfR.

One important problem in comparing the results of different studies in which the TfR assay was used to evaluate iron status is the wide range of reported values for this measure among laboratories and among different commercial assays (21, 22). Although numeric values obtained with the different TfR assays may differ, they have good correlation and similar abilities to identify iron deficiency if the reference values for that particular assay are used (22–27).

In the group of infants studied, which included iron-sufficient subjects and subjects with different stages of iron deficiency, TfR:SF was normally distributed when converted to a logarithmic scale. Normal distribution of log TfR:SF was also described in pregnant women living in Kingston, Jamaica (N Ahluwalia, unpublished observations, 1993). These results suggest that the current definition of normal and iron deficient is arbitrary and that body iron status is a normally distributed continuum. Our results highlight the difficulty in trying to define iron status.

Usually the performance of a test is measured by calculating the sensitivity and specificity of an optimal cutoff that is based on defining the central 90% or 95% CI of the distribution of test values of a population sample defined as normal. The goal of a diagnostic or screening test is to have both high sensitivity and high specificity. ROC curve analysis is an alternative, useful method for determining the best indicator of a certain health status. In our study, the performance (combination of sensitivity and specificity), measured by ROC curves, of TfR and TfR:SF was better than that of SF in detecting iron deficiency. Furthermore, TfR:SF > 975 and SF < 10 µg/L showed a similarly adequate sensitivity of 68.4% and 63.7%, respectively, and satisfactory specificity of 63.3% and 60.8%, respectively. TfR showed a low sensitivity (23.6%) and good specificity (98.3%). However, its sensitivity improved when a TfR > 10 mg/L was selected as the cutoff (sensitivity: 66.5%; specificity: 71.3%). The sensitivity of TfR in the present study disagrees with the findings in adults of 69% to 94% (24–27). The disagreement in the sensitivity and specificity of TfR observed between our study in infants and studies in adults could be attributed to differences in the criteria used to diagnose ID and to the considerable overlap of TfR values between iron deficient infants and infants with a normal iron status. This overlap may be related to a probably higher variability in the erythroid mass in healthy infants than in healthy adults.

We conclude that TfR and TfR:SF are associated with age-related changes and that TfR and TfR:SF appear to be better indicators of iron deficiency in infants than is SF. Because the performance of TfR and TfR:SF are similar in detecting iron deficiency, TfR seems to be the best isolated measure of iron status in infants. TfR is not an adequate indicator because of its lower sensitivity and high cost; however, its high specificity makes it satisfactory for confirming the presence of iron deficiency. One of the main problems remaining is the assessment of iron status in groups with high prevalences of infection. Both SF and TfR:SF are affected by acute or chronic inflammation. However, because TfR concentration is not affected by acute or chronic inflammatory conditions (2, 3, 25, 28), the measurement of TfR continues to be a useful tool in the assessment of iron status in groups with high prevalences of infection.


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Received for publication October 13, 1999. Accepted for publication April 20, 2000.


日期:2008年12月28日 - 来自[2000年72卷第5期]栏目
循环ads

母婴铁代谢研究进展

  摘要 目的:孕妇、婴儿是铁缺乏症主要的高危人群。综述胎儿铁代谢特点及母婴铁代谢关系。方法:收集有关小儿铁缺乏症近年的研究资料加以综合归纳。结果:从分子水平阐述了孕母对胎儿铁代谢影响的理论依据。结论:围产期防治缺铁十分重要。

  关键词 铁代谢;孕妇;婴儿;缺铁

  中图分类号 R723.2

  铁是人体重要微量元素,体内贮存铁减少,不仅引起贫血,而且含铁酶和铁依赖酶活性降低引起非造血系统表现,对人体智力、体格发育、免疫功能、消化吸收功能、劳动能力等均有较大影响[1],已被世界卫生组织(WHO)列为全球四大营养性疾病之一。孕妇、婴儿是主要的高危人群,近年围产期铁代谢研究有新的进展,为母婴铁缺乏症(IDD)的防治提供了重要理论和实践依据。

胎儿期铁代谢特点

  胚胎从第四周开始具有造血细胞的能力,胎儿体内铁随其体重和血容量增加而增加,所以胎儿在孕期后三个月获得铁最多,每日可从母体获得4mg铁,故早产儿更易发生缺铁。胎儿从母体是主动获取铁,即孕母的铁经胎盘可呈逆浓度梯度进入胎儿体内,胎盘绒毛膜上皮细胞通过受体介导将孕母转铁蛋白(Tf)和铁蛋白(Fn)中的铁运至胎盘中而后供给胎儿合成血红素、肌红蛋白和含铁酶等。总铁量的75%运至骨髓幼红细胞合成血红蛋白(Hb),25%以Fn和含铁血黄素(Homesiderin)贮存在肝、脾。由于胎儿期动用铁必须的黄嘌呤氧化酶活性低,铁一旦被贮存则不易被动用。

  正常情况下,铁总是从母体送给胎儿,保持胎儿体内铁含量恒定在75~80mg/kg之间,这样,足月新生儿从母体得到的铁一般足够生后4个月之用。无论孕母有无缺铁其所生婴儿在生后一周岁内Hb及新生儿期铁蛋白量均无显著差异,孕母铁状况对其乳铁蛋白量的影响也极微。孕期特别是怀孕晚期(最后三个月)孕母常有缺铁,补铁对母体的好处大于胎儿或婴儿。有学者为了增加婴儿内源性铁量,做对照研究表明,接生时注意置初生儿低于胎盘40cm,并于脐动脉停搏后30秒断脐,可能增加血量75~125ml(为新生儿血量的1/4~1/3),铁量40mg左右,因每毫升血含铁0.5mg,故可大大增加新生儿体内铁含量。

孕母与胎儿铁营养关系

  妊娠期间,由于胎儿经胎盘从母体摄取大量的铁供其生长发育所需,因而孕妇容易发生铁代谢紊乱而出现缺铁。那么,孕母缺铁是否对胎儿的铁营养状况有影响呢?这是一直存在的一个有争议的学术问题。归结起来有两种学说,即“无私”论和“有限无私”论学说。80年代中期以前多数学者赞成“无私”论学说,认为孕母无论铁缺乏症如何严重总是继续无私地向胎儿供铁,即孕母铁营养状况不影响胎儿按其自身的需要从母体获取铁。80年代后期大量的研究,越来越多的学者赞同“有限无私”论学说,认为孕母缺铁到一定程度会影响胎儿铁营养状况。Colomer等的前瞻性队例研究发现缺铁性贫血(IDA)孕母的胎儿生后一年内IDA发病率明显高于正常孕母所生婴儿,并认为可能与胎儿期贮存铁不足有关。Sigla等[2]发现严重IDA孕妇(Hb≤60g/L)其新生儿脐血血清铁显著降低,且重度IDA孕妇所生新生儿体重低于正常对照。表明孕妇严重缺铁可影响红细胞生成期铁供应和新生儿体重。我们测定14例孕妇及所生新生儿铁营养指标发现,14例孕妇中11例有IDA,新生儿中有2例为IDA其孕母均为中重度贫血[3]。说明孕妇严重缺铁仍要影响胎儿铁营养。华西医大小儿血研究对中孕期(16~28周孕龄)胎肝可染铁及骨髓幼红细胞内外铁与孕妇铁缺乏之间关系进行了研究,结果表明:母体铁代谢状况正常者,中孕期胎肝内有一定数量的细胞外及细胞内铁贮存,进一步发现这种贮铁与孕母IDA有明显相关关系(r=0.5507,p=0.0061)。孕母隐性缺铁(LD)、轻度IDA和中度IDA各组胎肝铁粒幼红细胞比例显著低于正常。LD组虽明显低于正常组,但其比例仍达39.1%以上,而轻度和中度IDA组仅为正常对照的13.6%和13.4%(正常为83.2%)。胎肝细胞外铁与孕母铁缺乏有显著等级相关,随孕母铁缺乏加重,肝细胞外铁逐渐减少,中度IDA组肝细胞外铁全部阴性,提示母体铁代谢状况对胎肝铁贮存有明显影响[4]。

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  上述研究均表明孕母铁营养状况好坏对胎儿铁贮存有明显影响。在80年代未有更多学者赞同“有限无私”论学说。这一学说真正得到公认,还是在90年代对母婴铁代谢研究深入到分子水平,通过检测转铁蛋白受体(TfR)和铁蛋白受体(FnR)在胎盘微绒毛膜和幼红细胞膜的数量变化后,才在理论上根本解决这一学术问题,使这一学术上的争论画上一个句号。

母婴铁代谢的基础理论研究

  为了揭示母婴铁代谢的关系,解释孕母缺铁对胎儿铁贮存有影响的一些研究现象,80年代未和90年代初开始对IDD的研究深入到分子水平,该方面的研究,我国已走在世界前列。首先建立了检测TfR和FnR的方法,并明确在胎盘微绒毛膜、肝细胞膜、幼红细胞和幼红细胞内线粒体上均存在TfR和FnR[5、6]。Fe3+最终与TfR或FnR结合进入线粒体,在亚铁络合酶的作用下与原卟啉IX合成血红素。TfR和FnR的发现揭示了胎盘铁转运机制。

  转铁蛋白(Tf)是体内运铁的主要蛋白,TfR介导Tf进入细胞内。TfR分子量为180000的跨膜糖蛋白,由分子量为90000的2个亚基组成,每个亚基可与1个Tf分子结合。TfR广泛分布于铁代谢旺盛和增殖活跃的细胞如幼红细胞、网织红细胞、肿瘤细胞及胎盘滋养层合体细胞上。妊娠过程中,有大量的铁逆浓度梯度经胎盘转运给胎儿,主要是胎盘TfR介导转运的结果。孕母血浆中Tf结合于胎盘绒毛膜滋养层合体细胞顶端的TfR上形成Tf—TfR复合物,该复合物经受体介导的胞饮作用被摄入细胞,在细胞内释放出铁后,来自母体的Tf再回到母血循环中,而摄入细胞内铁则可能通过Cytoferrin(一种低分子量结合物)介导或其它尚不清楚的途径,跨过合体细胞基膜与胎儿Tf等结合进入胎儿血循环。1988年Adams等人首先从人的肝细胞膜上分离纯化出铁蛋白受体(FnR),其分子量为53000。铁蛋白的亚基与胞膜上的FnR糖化后结合形成铁蛋白———受体复合物(Fn—RC),通过受体介导胞饮作用进入胞浆。Fn—RC在胞浆内与溶酶体融合后,铁从Fn中释放出来,部份Fn被降解,其余以去铁Fn—RC形式返回细胞外,完成膜循环过程[5、7]。还有学者认为线粒体膜上亦存在FnR,体外研究证实后作为载体将铁转运入线粒体,这一转运过程必须Fn与受体结合后才能实现[7]。

  近年国内学者廖清奎等[8、9、10]通过测定孕母骨髓幼红细胞和胎盘微绒毛膜及胎儿幼红细胞膜上的TfR和FnR位点数目变化表明,母胎间的铁代谢关系是“有限无私”的。在妊娠中期,孕母隐性缺铁时,胎肝幼红细胞TfR表达与正常组无明显差异,当孕母轻变IDA时,胎儿骨髓幼红细胞TfR表达明显高于隐性缺铁组和正常组。提示中孕期孕母隐性缺铁(LD)对胎儿骨髓造血尚无明显影响,但轻度IDA时,胎儿骨髓已出现了相应代偿性变化。对中孕期胎盘TfR研究发现,中期孕LD时胎盘TfR数明显升高,轻度IDA对胎盘TfR数开始下降,但仍高于正常,表明中孕期胎盘对铁转运功能较弱,TfR变化受孕母缺铁影响显著[8]。在妊娠晚期,孕母LD或轻度IDA时其幼红细胞膜TfR和FnR数目降低,而胎盘微绒毛膜以及胎儿幼红细胞膜上TfR和FnR位点数明显增加,由于胎盘和胎儿的TfR和FnR的强大数量优势,可保证胎儿按其需要从母体摄取铁。当孕母中度IDA时则胎儿幼红细胞膜及胎盘的TfR和FnR位点数降至正常水平,而孕母幼红细胞膜上TfR和总第26期FnR位点数明显增加,使胎盘和胎儿的TfR、FnR数量优势减弱,胎儿铁的供给受到影响[11]。近期的研究进一步确定中期孕胎盘FnR表达已基本成熟,胎盘微绒毛膜FnR在母体向胎儿铁转运过程中的作用是摄取母血中的铁蛋白铁供给胎儿,以保证胎儿的铁代谢和铁储存,孕母IDA时经胎盘的铁转运减少[12、13]。这些研究结果表明,“有限无私”论学说能高度概括母———婴铁代谢的关系。

结 语

  从IDD患病规律看,我国存在着一条链环模式的铁缺乏社会群体。这就是孕妇铁缺乏———婴幼儿铁缺乏———少女铁缺乏———孕妇铁缺乏……如此周而复始。可见,婴幼儿和孕妇是IDD最主要的高危人群,是防治的重点之重。婴幼儿出生后1~2年内,其Hb内铁的70%和40%是胎儿期从母体摄取,而母亲在孕期供给胎儿、胎盘及脐带生长所需的铁高达375~475mg。母婴铁代谢的研究表明,孕妇铁代谢紊乱不同程度上影响胎儿铁代谢[12]。因此,防治孕期缺铁无论是对孕母和新生儿均是有益的。对孕期IDA应高度重视,采取防治结合,防重于治的方针,并将婴幼儿IDD的防治从围产期开始。

  参考文献略

日期:2004年9月29日 - 来自[生理学]栏目
共 1 页,当前第 1 页 9 1 :

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