J Clin Pathol: first published as 10.1136/jcp.s3-5.1.55 on 1 January 1971. Downloaded from J. clin. Path., 24, Suppl. (Roy. Coll. Path.), 5, 55-59 Haemopoietic factors Iron absorption A. JACOBS Department of Haematology, Welsh National School of Medicine, Cardiff Physiological control over iron balance is normally porated in corn or black beans is better absorbed exercised through the regulation of iron absorption. when eaten with either veal or fish (Layrisse, Although it is known that the intestinal epithelium Martinez-Torres, and Roche, 1968). The stimulating can reject unwanted dietary iron or absorb increased effect of fish on iron absorption from black beans amounts when stores are low it is not known how iron appears to be due to the presence of cysteine in the crosses the epithelial cell or how this regulation is digestive products of the fish (Martinez-Torres and mediated. The principal factors which affect absorp- Layrisse, 1970). tion are those acting in the lumen of the gastro- The fate of ionizable iron released from food in intestinal tract which determine availability of iron the gut lumen is largely determined by its chemical for mucosal uptake, intraepithelial mechanisms reactions. Ferric ions undergo increasing poly- controlling iron transit across the mucosa, and merization forming colloidal gels as the pH rises changes within the body which signal iron require- towards neutrality and finally form a precipitate of ments to the intestinal cells. ferric hydroxide. Ferrous irons do not undergo such marked polymerization and their solubility is greater copyright. Intraluminal Factors than ferric irons at any given pH which accounts, at least partly, for their greater availability. The un- Much work on iron absorption is related to the polymerized ions of both species found at low pH behaviour of simple inorganic iron salts and although are chemically reactive and when the gastric contents the data obtained are relevant to normal physio- pass into the jejunum and neutralization occurs they logical mechanisms the absorption of iron from food combine with available ligands to form complexes. introduces some complications. Probably the most Iron binding in this situation may result in the forma- important factor affecting total food iron absorption tion of insoluble complexes such as those with http://jcp.bmj.com/ is the iron content of the diet itself. A recent survey phytate or phosphate, or it may produce complexes in Cardiff showed that a mean daily iron intake of such as ferrous ascorbate which are available for 17-5 mg in men and 14-1 mg in women, though the absorption. Under normal circumstances the largest range of dietary iron was from 6 to 27 mg a day. The part of the iron-binding capacity of gastric contents amount of food iron which is available for absorp- is provided by the gastric secretions themselves. tion depends primarily on the amount released by Haem iron released from food in the stomach the digestive process. Less than half the total iron in appears to enter the intestinal epithelial cells un- on October 1, 2021 by guest. Protected food is released by peptic digestion in the stomach changed. When neutralization of gastric contents and this is largely in the form of ionizable inorganic by pancreatic juice occurs the polymerization of iron except in the case of meat where iron is released haem is prevented by the presence of other protein as the haem complex. The amount released is con- degradation products and these help to maintain its siderably reduced in subjects with gastric atrophy availability to the mucosal cells (Conrad, Benjamin, (Jacobs and Miles, 1969a). Direct measurements of Williams, and Foy, 1967). The availability of haem iron absorption from foodstuffs, using foods labelled iron is uninfluenced by the various intraluminal biologically with radioactive tracers, show consider- factors which affect ionizable iron. able variation, mean absorption being about 10 %. Iron availability is not only related to the particular GASTRIC JUICE food source but also to the interaction with other There is much conflicting evidence regarding the role foods and with gastrointestinal secretions. For of gastric juice in iron absorption but there seems example, iron absorption from veal is inhibited by little doubt that hydrochloric acid itself plays an the presence of corn or beans whereas iron incor- important part (Jacobs, Bothwell, and Charlton, 55 J Clin Pathol: first published as 10.1136/jcp.s3-5.1.55 on 1 January 1971. Downloaded from 56 A. Jacobs 1964). Hydrochloric acid secretion maintains the STOMACH pH2 JEJUNAL LUMEN pH 5 MUCOSA r~~~~~~~ir I low pH necessary for the peptic digestion of food -~~~~~~~~I and ensures that released iron remains in a chemi- cally reactive form which can produce soluble complexes. A number of workers have suggested that gastric secretions contain an intrinsic factor for iron (Koepke and Stewart, 1964; Murray and Stein, 1967). This factor was thought to promote the absorption of iron by the small intestine and variations in its secretion were thought to be responsible for the physiological control of iron absorption in iron- deficient and iron-overload states. Davis, Luke, and Fig. I Possible reactions of inorganic iron in the Deller (1966) demonstrated in gastric juice an iron- gastrointestinal lumen. In normal circumstances it is binding substance with a high molecular weight, probable that most iron follows the lowest pathway. which they called gastroferrin, and they suggested that this was a physiological inhibitor of iron Conrad, 1967; Kavin, Charlton, Jacobs, Green, absorption. Haemochromatosis was considered to Torrance, and Bothwell, 1967). Balcerzak, Peternel, be an inborn error of metabolism in which there was and Heinle (1967) have suggested that the increase a failure to secrete gastroferrin and in iron-deficiency in iron absorption sometimes found in chronic anaemia there was said to be a similar decrease of pancreatitis is due to a number of possible artifacts secretion allowing an increased absorption of dietary the most important of which is coexistent iron iron. Neither the intrinsic factor nor the gastro- deficiency. Olatunbosun, Ludwig, Corbett, Simon, ferrin hypothesis has been supported by the observa- and Valberg (1970) have similarly shown that the tions of other investigators (Jacobs, Rhodes, and increased iron absorption found in portal sclerosis is Eakins, 1967). usually associated with decreased iron stores. copyright. Experiments in vitro with human gastricjuice show The importance of pancreatic secretions in iron that it has the ability to form a complex with absorption is an indirect one. The breakdown of ionized iron which remains soluble at neutral pH. polypeptide chains by pancreatic enzymes results in In order for this complex to be formed the iron and the appearance of amino acid and dipeptide mole- gastric juice must mix at acid pH and be followed by cules in the upper jejunum. Conrad et al (1967) have neutralization, the normal sequence of events. The shown that the absorption of pure haem in iron is iron-binding fraction of human gastric juice has a relatively poor unless protein degradation products are also molecular weight in excess of 200,000 and is prob- present to prevent polymerization of the http://jcp.bmj.com/ ably a mucopolysaccharide (Jacobs and Miles, haem complex. It is possible that amino acids may 1969b). The amount of iron-binding substance also be important in removing ionizable iron from secreted by the stomach does not differ from normal the high molecular weight mucopolysaccharide in either iron-deficiency anaemia or haemochro- complex which forms on the neutralization of gastric matosis. contents to form low molecular weight complexes Under normal circumstances most of the ioniz- which are available to the intestinal mucosa (Fig. 1). able iron released from food in the stomach either Studies in vivo and in vitro suggest that this is binds to the mucopolysaccharide in the gastric certainly the case for cysteine (Jacobs and Miles, on October 1, 2021 by guest. Protected secretions or becomes unavailable on neutralization 1969a; Martinez-Torres and Layrisse, 1970). Bile (Fig. 1). Only in exceptional circumstances, when a may play a small part in promoting iron absorption meal contains large amounts of a chelating agent, but the suggestion that this is due to its ascorbic such as ascorbic acid or citric acid, do other low acid content has not been supported by our own molecular weight complexes form. observations (Jacobs and Miles, 1970). PANCREATIC AND BILIARY SECRETIONS The Mucosal Cell There is no clear evidence that pancreatic extracts or juice have any special effect on iron absorption Intraluminal factors in the gastrointestinal tract (Murray and Stein, 1966). Bicarbonate is known to affect the availability of ionizable iron for uptake by promote the formation of macromolecular iron epithelial cells but they play no part in the physio- complexes when free iron is present but no consistent logical regulation of iron absorption. Iron which is effect of bicarbonate on iron absorption has been destined to pass across the small-intestinal mucosa found experimentally (Benjamin, Cortell, and and enter the circulating plasma does so very rapidly J Clin Pathol: first published as 10.1136/jcp.s3-5.1.55 on 1 January 1971. Downloaded from Iro n absorption 57 after its uptake by the epithelial cells. Halberg and pylorus to the terminal ileum but serosal transfer Solvell (1960) have shown that after a single oral was largely limited to the duodenum. Wheby and dose of iron most of the absorbed portion had Crosby (1963) showed that after a gastric dose of entered the blood stream within two hours. Wheby labelled iron the maximal uptake was in the first and Crosby (1963) have shown a similar rapidity quarter of the small intestine. Uptake was greatest of absorption after the intragastric administration in iron-deficient animals and least in iron loaded of iron in rats.