Gut: first published as 10.1136/gut.30.12.1686 on 1 December 1989. Downloaded from Gut, 1989, 30, 1686-1691 Vitamin B12 absorption and malabsorption H SCHJ0NSBY (This article is one of a series linked with the Festschrift for Christopher Booth. See Gut Festschrift 1989; 30.) When radioactively labelled vitamin B12 became R-protein in the stomach; (2) degradation of the R- available after 1950, it was soon established that binder by pancreatic proteases and binding of B12 by patients with lesions of the distal small bowel may be intrinsic factor in the upper small bowel. unable to absorb normal amounts of vitamin B12 and It has been shown in vivo that there is a rapid may develop megaloblastic anaemia.' 2 These release of vitamin B12 from food in the stomach.6 observations suggested that ileum is the site of This release is facilitated by acids as well as pepsin.6 vitamin B12 absorption. Direct evidence was pro- The dependence of this release on peptic digestion vided in 1959 by Booth and Mollin,3 who studied the may, however, only apply to some food sources. distribution of radioactivity in the intestine after oral Cooking and food preparation may play a role, and administration of labelled B 12. Using a Geiger Muller from some food sources, including liver, vitamin B12 counter during laparotomy, radioactive B12 was is readily released even when the pH of the stomach is found concentrated in the ileum. Vitamin B12 is neutral.6 unique in several respects; it is absorbed only in the It was thought until recently that vitamin B12, after ileum in contrast with most other substances; it its release from food proteins, attached to gastric requires a gastric intrinsic factor to be efficiently intrinsic factor (IF). There is now evidence that absorbed; and because the number of specific cobalamins preferentially binds in the acid stomach receptor sites in the ileum is restricted, only tiny to another B12-binding protein, R-protein or hapto- amounts can be absorbed. There is also a delay in the corrin. R-proteins are found in many body fluids transport from the lumen across the enterocyte until including saliva, gastric juice, bile, intestinal juice, the vitamin appears in the plasma,4 which may be the and serum. Allen et al in 1978' showed in vitro that result of metabolic processes within the enterocyte. human salivary R-protein bound cobalamin (Cbl) In recent years there have been several studies which with affinities that were 50- and three-fold higher have enhanced our understanding of vitamin B12 than those of human IF at pH 2 and pH 8 respect- absorption and malabsorption, and the aim of this ively. Incubation of the R-protein-cobalamin http://gut.bmj.com/ review is to concentrate on recent developments. complex with pancreatic proteases led to complete and rapid transfer of cobalamin to intrinsic factor. Normal vitamin B12 absorption From these studies it was suggested: (a) that in the acid milieu of the stomach Cbl is bound almost Methylcobalamin, deoxyadenosylcobalamin and exclusively to R-protein rather than to IF; (b) that hydroxycobalamin are the major forms of cobalamin Cbl remains bound to R-protein in the small intestine (vitamin B12) in different food sources. The until pancreatic proteases partially degrade R- on October 1, 2021 by guest. Protected copyright. cobalamin used in clinical studies, cyanocobalamin, is an artifact of the isolation procedure. Vitamin B12 cannot be synthesised by mammalian species, but Table 1 Phases of vitamin B12 absorption only by microorganisms. In man bacterial synthesis in caecum. 1 Intragastric events takes place only the large bowel and the a Release of B12 from food proteins From these sites absorption cannot take place, and b Binding of BI2 by R-protein therefore man is entirely dependent on dietary 2 Duodenal andjejunal events sources of vitamin B12. The richest natural sources a Degradation of R-protein by pancreatic proteases b Binding of B12 by intrinsic factor are liver and kidney, but vitamin B 12 is also present in 3 Ileal events meat, fish, dairy products, eggs, and shellfish. The a Attachment of B 12-IF to receptor average daily intake is about 3 nmol (4 rig), whereas b Transport of B12 across enterocyte the physiological needs are 0.4 to 0.8 nmol (0.5-1.0 c Binding of B12 by transcobalamin II in portal blood 4 Enterohepatic circulation itg) a Biliary excretion of B12 and B12-analogues bound by R- The absorption of vitamin B12 appears to result protein from an orderly sequence of events.5 These events b Degradation of R-protein by pancreatic proteases and are shown in Table 1. The events before ileal absorp- formation B12-IF c Ileal reabsorption of B12 and faecal excretion of B12- tion include: (1) the release of vitamin B12 from its analogues binding by dietary protein, and the binding of B12 to 1686 Gut: first published as 10.1136/gut.30.12.1686 on 1 December 1989. Downloaded from Vitamin B12 absorption and malabsorption 1687 protein and enable Cbl to become bound exclusively highly significant rise in mitochondrial radioactivity to IF. Results of a recent in i'i'o study support that during two hours postfeeding. This activity subse- B12 preferentially binds to R-protein in the stomach quently decreased coincidentally with a rise in and is transferred to IF in the upper small bowel.b hepatic specific activity. Although this suggests that Liver homogenate labelled in vivo with '7Co was vitamin B12 is delayed in the mitochondria before the administered orally to healthy volunteers. It was vitamin enters the portal plasma, the metabolic found that approximately two thirds of the radio- events within the mitochondria during the delay active vitamin B12 in the gastric aspirate was bound to remains to be elucidated. R-protein and one third to intrinsic factor, whereas in When vitamin B12 leaves the enterocyte and enters jejunal aspirates only 25% was bound to R-protein. the portal plasma, it is bound to transcobalamin II, The degree of binding to R-protein and intrinsic but whether binding to transcobalamin 11 occurs factor in the stomach, however, may be dependent within the enterocyte or in the plasma is not clear. on the oral dose of vitamin B12, the amounts of R- Studies in volunteers by Chanarin et al'4 suggest protein and intrinsic factor secreted, and the gastric indirectly that vitamin B12 enters blood bound to pH. transcobalamin II, which may be derived from the The vitamin B12-intrinsic factor complex is carried ileal enterocyte. Transcobalamin II may also be to its site of absorption in the ileum, where it attaches essential for normal absorption of vitamin B12, as to specific membrane receptors. The attachment is malabsorption of the vitamin has been described in highly specific, and the receptor does not take up association with congenital deficiency of trans- vitamin B12 bound to binders other than intrinsic cobalamin II.`, factor nor does it take up vitamin B12 analogues. The An enterohepatic circulation of vitamin B12 has binding site on vitamin B12 for intrinsic factor is been suggested because the amount of vitamin B12 separate from that which attaches to the receptor.' excreted in the bile is much higher than that excreted This is supported by the report of a child who in the urine and the faeces. The biliary B12-secretion developed vitamin B12 deficiency as a result of an involves about 3 nmol (4 [tg) all bound to bile abnormal intrinsic factor.' This abnormal intrinsic R-binder. Of the total amount of corrinoids in the factor bound vitamin B12 normally and also reacted bile more than 50% may represent vitamin B12 appropriately with antibody to intrinsic factor, but analogues.' The bile R-protein is thought to be the abnormal intrinsic factor - vitamin B12 complex degraded by pancreatic enzymes with transfer of failed to attach to the ileal receptor. The attachment vitamin B12 to intrinsic factor in the upper small to the receptor is non-energy dependent and requires bowel. Although the exact amount is unknown, http://gut.bmj.com/ the presence of calcium-ions and a neutral pH. The more than half of the biliary vitamin B12 may be receptor which has not been fully characterised, has reabsorbed, whereas the analogues that do not bind been located at the bottom of the pits between the intrinsic factor, are excreted. The enterohepatic microvilli,9 and has been shown in the entire distal circulation therefore seems to play a major role in three fifths of the human small intestine."' conserving vitamin B12; in addition the bile is the The number of B12-receptors may be the rate of major excretory route for vitamin B12 analogues. limiting step in the absorption of vitamin BI2 and as It is also possible that bile itself may play a role on October 1, 2021 by guest. Protected copyright. shown in Booth's laboratory may show an adaptive in enhancing vitamin B,2 absorption. This was increase in response to jejunal pathology." suggested from studies by Teo et al`s who observed How cobalamins are transported across the entero- B12-malabsorption in five patients with T-tube bile cyte is not fully understood, and the fate of intrinsic duct drainage, which improved after the T-tubes had factor is also unclear; intrinsic factor is not absorbed been removed. Whether bile or bile acids play a role into the blood, and may either be transported into the in physiological B12-absorption is, however, not cell along with vitamin B12, or it may be released at clear, although it has been proposed that bile acids the cell surface.