EDITORIALS REGULATION OF IRON ABSORPTION

Transcription

1 GSTROETEROOGY Copyright 1966 by The Williams & Wilkins Co. Vol. 50, o.6 Printed in U.S.. EDITORIS REGUTIO OF IRO BSORPTIO lthough a number of factors influence the amount of dietary iron absorbed, regulation of iron absorption is a function of mucosal epithelial cells of the small intestine. Variation in the absorptive capacity in response to body iron requirements was first suggested by McCance and Widdowson l and demonstrated by Hahn and coworkers.2 Both of these groups considered the iron content of intestinal epithelial cells to be important in regulating absorption. The latter group introduced the controversial concept of "mucosa block" and postulated that it was related to "physiological saturation" of a mucosal cell receptor for iron which they speculated to be ferritin or its protein precursor, apoferritin. Whether ferritin is involved in the absorptive process remains unsettled, but recent studies have focused again on mucosal cell iron content as the most important factor in determining the cell's capacity to absorb iron. 3-6 In a series of studies,3-5 Conrad, Weintraub, and Crosby demonstrated that in response to challenges known to alter iron absorption, changes in absorption correlated inversely with changes in the iron content of intestinal tissue. Following acute blood loss, enhanced absorption was noted concurrently with decreased intestinal content of iron.4 Conversely, subsequent to parenteral injection of iron, depression of absorption was most.marked when injected iron was maximally concentrated in the intestinal tissues. 5 Radioautographs made after parenteral injection of iron-59 suggested that injected iron was concentrated in newly formed cells in the intestinal crypts, and remained in the cells for their life_span. 3 5 On the basis of these observa- ddress requests for reprints to: Dr. Munsey S. Wheby, Department of Medicine, Rutgers Medical School, ew Brunswick, ew Jersey. 888 tions, it was postulated that the absorptive capacity of each mucosal cell is determined by the amount of iron incorporated into the cell when it is formed in the crypts of ieberkuhn. Furthermore, according to this hypothesis, the amount of iron incorporated is dependent on plasma iron clearance which reflects the body's iron requirements, most of which is utilized for hemoglobin synthesis. When an increase in erythropoiesis occurs, increased amounts of plasma iron are diverted to the bone marrowand, consequently, less iron is incorporated into newly forming mucosal cells. s a result, the cell's absorptive mechanism is less inhibited and an increase in the absorptive capacity occurs. This hypothesis explains the repeatedly observed close relationship between marrow erythroid activity and iron absorption. 7 It also explains the usual lag period between a challenge and subsequent response of the absorptive mechanism. 2,7 For example, following an acute bleeding, 4 to 5 days elapse before increased erythroid activity produces a change in plasma iron kinetics which, according to the hypothesis, must first occur to influence the newly forming cells in the intestinal crypts. 4, 5 dditional time is required for the influenced cells to move from the crypts out onto the absorptive portion of the villus although within 2 to 3 days they can replace completely the older, uninfluenced population of cells. s The evidence in support of this hypothesis is convincing. However, if we accept the concept that the absorptive capacity is determined when the mucosal cell is "born," we must explain those studies which show that the absorptive capacity is influenced also by the cell's exposure to iron in the intestinal lumen. Pre-feeding iron exerts an inhibitory effect on subsequent absorption ;2, 6, 9-11 the inhibition appears to be a

2 June 1966 EDITORIS 889 direct effect of iron on the intestine; is proportional to the amount of iron in the pre-feeding; and persists for up to 17 hr.1o Recent observations on the mucosal mechanisms for absorbing iron indicate an interaction between the regulatory effect of iron incorporated into the newly formed cell and iron which later enters the cell during its absorptive period. This interaction affects the iron content of mucosal cells and presumably, therefore, their capacity to absorb iron. The absorptive mechanism for elemental iron, in man and animals, consists of at least three components3, 6, (fig. 1): component, mucosal uptake of iron from the lumen; component B, mucosal transfer of iron to plasma; component C, mucosal storage of iron. Components and B are distinct steps and each has features of an active transport system Together they comprise a rapid transport process which, within 2 to 4 hr after onset of absorption, transfers up to 80% of the iron ultimately absorbed into plasma This process is not dependent on availability of unsaturated plasma iron-binding protein in man 16 or animalsp In this system, iron is in the divalent, ferrous state,6 but further characterization remains unsettled Component C is a system which incorporates iron into a storage form, apparently in the ferric state,6 which is released slowly, if at all. Evidence has been presented for 12 and against 6 18 ferritin as the storage form and this remains controversial. Whatever the form, the amount of iron handled in this manner is important on two counts. First, much of this iron is not transferred to plasma but remains within the mucosal cell and is lost when the cell is sloughed at the villus tip as proposed by Conrad and Crosby.3 t times, a considerable amount of the iron which enters mucosal cells during absorption is stored and lost in this fashion,12 13 Second, if the iron content of a mucosal cell determines its absorptive capacity, to the extent that iron entering mucosal cells from the lumen is stored, the cell's absorptive capacity will be decreased. Current evidence6, indicates that the amount of ingested iron available for mucosal cell storage during absorption depends on the amount of iron fed, and the relationship I T E S T I U M E MUCOS CEll f : ' ~ ~ 1 IRO ODED IRO DEFICIET P S M FIG. 1. Proposed model of iron absorption. Each square represents a small intestinal epithelial mucosal cell. State of body iron is indicated. represents the active transport mechanism for mucosal uptake of iron from intestinal lumen. B represents the active transport mechanism for mucosal transfer of iron to plasma. C represents the mechanism for temporary storage of iron. The size of and B illustrate the relative transport rates. Both and B are related to body iron requirements, but is always greater than B. Iron is preferentially moved from to B to plasma, but depending on the amount of iron available to and the relationship of to B, a variable portion of the iron transported by moves to C for temporary storage. s indicated by the dotted arrow in normal and iron-loaded states, subsequent transfer of iron from C to plasma is very slow and may not occur before the cell is sloughed. C is dotted in the irondeficient mucosal cell to indicate that the efficiency of B is such that storage may not occur unless large doses of iron are used. Within limits, these transport and storage mechanisms regulate the amount of iron absorbed.

3 890 EDITORIS Vol. 50, o.6 between mucosal uptake of iron (component ) and mucosal transfer of iron to plasma (component B). The rate of mucosal uptake (), is always greater than the rate of mucosal transfer (B); however, the difference between the rates is not fixedy 14 lthough both are influenced by body iron requirements, mucosal transfer (B) is influenced to a relatively greater extent than mucosal uptake () Thus, when body iron requirements and the absorptive capacity are increased, the rate of mucosal transfer approaches the rate of mucosal uptake, so that ingested iron entering the cell is transported rapidly to plasma with little or no iron being available for the mucosal storage pathway (C) s a consequence, mucosal cell iron content is increased significantly for only a few hours after ingestion during the absorptive period when iron is in transit across the cell. This corresponds to the brief interval of decreased iron absorption found in irondeficient subjects following ingestion of large amounts of iron. 9 On the other hand, when body iron requirements and the absorptive capacity are decreased, the rate of mucosal transfer (B) is decreased more than the rate of mucosal uptake (), so that much of the iron entering cells is not rapidly transported to plasma, but becomes available for mucosal storage (C) Thus, the cell's content of iron is increased, perhaps for the rest of its life,3 and the absorptive mechanism is inhibited further. Hence, the interaction alluded to previously becomes evident: The amount of iron incorporated into newly formed cells establishes the base line inhibition, or regulation, of the absorptive mechanism,3-5 which, in turn establishes the relationship between mucosal uptake and mucosal transfery 14 Depending on this relationship and the amount of dietary iron presented to these cells, more or less iron will be stored in the cell during its life, thus adding to the inhibition, or regulation, of the mucosal cell iron transport system. In describing this effect of iron, Manis and Schachter6 proposed the term "self-inhibition" in preference to the older term, "mucosal block." The inhibitory effect of dietary iron has been shown, thus far, only in rats In view of the similarity of other characteristics of the iron absorptive mechanism in man and rat, this is most likely explained by the more precise methods of study and ease of dietary manipulation which can be applied to rats. However, this point, as with many of those already discussed, requires further investigation. The absorptive mechanisms described are operative for quantities of iron within limits which include the usual amount of dietary iron ingested. It is well known, however, that iron may traverse the gut in amounts sufficient to cause death. By administering increasing amounts of iron, it was shown that the regulating effect of the limited mucosal transport and storage mechanisms can be overwhelmed, and an apparently unregulated process with different kinetic characteristics, possibly passive diffusion of iron, supervenes 11 (fig. 2). In addition to the mechanisms discussed, other factors influence the amount of dietary iron absorbed. One important consideration is the fact that the duodenum and jejunum are the most efficient sites of iron absorption and are the most adaptive to body iron needs in man and rats Consequently, those factors are influential which affect the time during which iron is available for absorption at these sites. In addition to transit time, the iron content of the diet is of course quite important as is the dietary composition, in that certain substances, such as phosphates and phytates, form unabsorbable complexes with iron. Gastric acid, though not essential for iron absorption, does facilitate absorption of dietary iron. 23 Iron oxidized to the ferric state complexes readily with many substances and thus is not as available for absorption as the more labile ferrous form. Oxidation tends to occur in an alkaline environment such as that provided by biliary and pancreatic secretions. Some evidence has been presented which suggests that pancreatic extract, and presumably pancreatic secre tions, exert a suppressive effect on iron absorption. 24 Since the over-all effect of these

4 June 1966 EDITORIS 891 UME MUCOS PSM DOSE OF' IRO CE ~ : : I ~ :: I ~ : : : : : I FIG. 2. Illustration of the effect of increasing amounts of ingested iron on the regulatory function of the mucosal transport and storage mechanisms. mount of iron in the intestinal lumen is represented by the size of arrow on left. Each large square represents a small intestinal epithelial mucosal cell. Mucosal transfer of iron to plasma during the rapid phase of iron absorption is illustrated by arrow to right of mucosal cell symbol. s the dose is increased, mucosal transfer increases up to a limit as illustrated by the size of the arrows. The compartments within the mucosal cell indicate the iron storage capacity and each small block represents stored iron. Up to a limit the amount of iron absorbed into plasma is regulated by the transport and storage capacity of mucosal cells. When the limit is exceeded these mechanisms are overwhelmed and another process, possibly passive diffusion of iron, predominates, as indicated by the dotted arrows. mechanical and chemical factors is to limit the time during which iron is available for absorption, the importance of variations in the rate of iron transport by mucosal cells is magnified. This editorial has reviewed some of the current concepts of iron absorption and has emphasized the importance of mucosal cell iron content in regulating absorption. It is evident that before more complete understanding of the process is possible, much more information is needed on the identity of mucosal cell iron complexes. Munsey S. Wheby, M.D. Department oj Medicine Rutgers Medical School ew Brunswick, ew J ersey REFERECES 1. McCance, R., and E. M. Widdowson bsorption and excretion of iron. ancet 2: Hahn, P. F., W. F. Bale, J. F. Ross, W. M. Balfour, and G. H. Whipple Radioactive iron absorption by gastrointestinal tract; influence of anemia, anoxia, and antecedent feeding; distribution in growing dogs. J. Exp. Med. 78: Conrad, M. E., Jr., and W. H. Crosby Intestinal mucosal mechanisms controlling iron absorption. Blood 22: Weintraub,. R, M. E. Conrad, and W. H. Crosby The significance of iron turnover in the control of iron absorption. Blood 24: Conrad, M. E.,. R Weintraub, and W. H. Crosby The role of the intestine in iron kinetics. J. Clin. Invest. 43: Manis, J., and D. Schachter ctive transport of iron by intestine; mucosal iron pools. mer. J. Physiol. 207: Bothwell, T. H., and C.. Finch Iron metabolism, p ittle, Brown, and Company, Boston. 8. Bertalanffy, F. D Cell renewal in the gastrointestinal tract of man. Gastroenterology 43: Brown, E. B., R. Dubach, and C. V. Moore Studies in iron absorption and metabolism. XI. Critical analysis of mucosal block by large doses of inorganic iron in human subjects. J. ab. Clin. Med. 52: Manis, J. G., and D. Schachter ctive transport of iron by intestine: Effects of oral iron and pregnancy. mer. J. Physio!. 203: Wheby, M. S.,. G. Jones, and W. H. Crosby Studies on iron absorption; intestinal regulatory mechanisms. J. Clin. Invest. 43: Charlton, R. W., P. Jacobs, J. D. Torrance,

5 892 EDITORIS Vol. 50, o.6 and T. H. Bothwell The role of the intestinal mucosa in iron absorption. J. Clin. Invest. 44: Wheby, M. S., and W. H. Crosby The gastrointestinal tract and iron absorption. Blood 22: Manis, J. G., and D. Schachter ctive transport of iron by intestine: Features of the two-step mechanism. mer. J. Physiol. 203 : Hallberg,., and. Salvell bsorption of a single dose of iron in man. cta Med. Scand. 168 (Suppl. 358): Wheby, M. S., and G. Umpierre Effect of transferrin saturation on iron absorption in man. ew Eng. J. Med. 271: Wheby, M. S., and. G. Jones Role of transferrin in iron absorption. J. Clin. Invest. 42: Brown, E. B., and M.. Rother Studies of the mechanism of iron absorption. I. Iron uptake by the normal rat. J. ab. Clin. Med. 62: Bannerman, R. M., J. R. P. O'Brien, and. J. Witts Studies in iron metabolism. IV. Iron absorption in experimental iron defici ency. Blood 20: Pollack, S., R. M. Kaufman, and W. H. Crosby Iron absorption; the effect of an iron-deficient diet. Science 144: oyes, W., and P. H. Jordan Small bowel iron absorption in an unusual patient. Gastroenterology 46: Wheby, M. S Site of iron absorption in man. Clin. Res. 14: so. 23. Cook, J. D., G. M. Brown, and. S. Valberg The effect of achylia gastric a on iron absorption. J. Clin. Invest. 43: l. 24. Davis,. E., and J. C. Biggs The pancreas and iron absorption. Gut 6: