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1. Evaluation of methods for determination of absorption or retention It is felt by the present author, although agreement will not be universal, that balance studies constitute the standard by which the results of other methods should be judged. There are two ways in which iron balance has been determined. 1. The older chemical method which determines the difference between the iron ingested and that excreted in the feces. 2. The more recent method using radioactive iron which depends on determining the difference between the radioactivity ingested and that excreted in the feces. The chief drawbacks of the first method are (a) the difficulty and now the expense of carrying it out, and (b) the opportunity for inadvertent errors especially in the determination of intake; its advantage lies in the possibility of continued and repeated periods of observation. In spite of some stated opinions, there is no reason to believe that the methods for determining iron usually used are not as accurate as those using the radioactive technique. The radioactive method has the advantage of greater ease with the knowledge that one does not have to consider the possibility of the presence of traces of unaccounted iron; the chief disadvantage is the necessity to confine the determination to one observation in each subject. As a result there would be greater scatter and consequent uncertainty. A third method is that of inferring absorption from the amount of iron utilized for hemoglobin formation, depending on the assumption that if iron is not utilized for hemoglobin formation it will not be absorbed. Since this assumption is true only in limiited circumstances, the method based on it has only a limited application. About 15 or more years ago it was used extensively without proper control and as a result considerable error was introduced. A fourth method, that of determining the curve of serum iron following a test dose given by mouth, does not pretend to determine actual absorption, but rather is a method for comparison between groups. In the individual it is often used to determine capacity to absorb. While a high post absorptive curve could only mean good absorption a less high or flat curve does not necessarily mean a less good absorption unless it could be known that there was no diversion to the tissues. From a study of the rate of disappearance of intravenously injected iron it is concluded that differences in rate of diversion into the tissues is a factor that cannot be disregarded. 2. Factors influencing the absorption of iron. (a) Local factors. These factors, including such things as the effect of reducing agents, gastrointestinal acidity and motility, presence of phosphates, etc., were not specifically reviewed, although information pertaining to them will be found scattered through the review, and in the final section a few specific references to recent work have been included, especially where these might modify previously accepted notions. (b) General factors. 1. Diet. There is no section devoted particularly to diet, but a discussion of many of the dietary factors, especially those of importance in the feeding of infants, will be found in section B and C. A fact that has been known for the past twenty years is confirmed by recent work, that inorganic iron supplementation is a more effective way of increasing iron retention than giving iron in the form of vegetables. Supplementation with inorganic iron is often inadvertently accomplished in the commercial preparation of processed foods, so that these foods may be a factor in effectively increasing the iron intake. The most potent factor in increasing absorption of iron is iron deficiency anemia. For a time it was generally believed that storage depletion was responsible for the result; while storage plethora caused reduction in absorption. More recently, however, the evidence has favored hemoglobin reduction rather than storage depletion as the responsible factor. This has been confirmed by recent work indicating the importance of anoxia in mobilizing iron from ferritin storage. A third possibility, that of increased hemopoietic activity, has also been suggested. Whether or not there is actually such a thing as a "mucosal block" acting as a mechanism for excluding excess iron is not to be decided by any review. There have been found so many exceptions to any such mechanism that there hardly seems any area of activity left except possibly in explaining the unimpeded absorption of iron in the presence of anemia, compared with the slower absorption in the normal. 3. Pathways of distribution and , final disposition of absorbed iron. Iron entering the body by absorption takes certain definite pathways which initially differ from those taken by injected iron. It enters by way of the mucosal cell in which its combination in ferritin is a form of temporary storage from which it is passed on to the plasma at a rate that ordinarily does not cause increase in the level of plasma iron. At such a rate it apparently is taken up almost entirely by the bone marrow to be used to replace the small quota of iron derived from daily breakdown that ordinarily escapes the "hemoglobin cycle." When absorbed in amounts sufficient to raise the plasma iron level appreciably, or when hemopoietic activity is reduced, it is taken up by the liver where it is stored or rerouted to the bone marrow dependinig on the latter's capacity to use it. If hemopoietic activity is raised, the absorbed iron seems to by-pass the liver completely (physiologically, not anatomically) and to go directly to the marrow, in spite of a rise in plasma iron level that would ordinarily lead to a considerable deposition in non-hemopoietic tissue. Intravenous iron is in general more rapidly and completely utilized for hemoglobin formation than is iron given by mouth even when this is adequately absorbed. The reason for this may be in differences in the primary distribution of iron depending on the portal of entry. Iron absorbed by the gastroinstestinal route in amounts larger than can be immediately utilized in hemoglobin formation is deposited predominantly in parenchymal liver cells, whereas intravenously injected iron is deposited principally in reticuloendothelial cells, along with the iron derived from breakdown of hemoglobin. It is this latter iron that is generally available for the day to day synthesis of hemoglobin. It is suggested that the iron deposited in liver parenchyma mainly in the form of ferritin, has a different function, namely that of serving as a reserve, mobilized under conditions of anoxia and specifically sensitive to reduction in level of hemoglobin.