Intrinsic factor Subject

Nutritional Deficiency-Related Dementias. We have already mentioned that chronic alcoholics are subject to thiamine deficiency that can cause dementia. It usually occurs only after heavy, prolonged abuse of alcohol. In developed countries, the other key nutritional concern is vitamin deficiency. Vitamin deficiency can surprisingly strike even those with a healthy diet. Such people are missing a vital protein, intrinsic factor, which would enable them to absorb it from their digestive tract. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

Vitamin B12 can be absorbed when present in physiological amounts only if it is first bound to a specific protein—the so-called intrinsic factor—that tightly binds to the vitamin. The complex then passes through the jejunum to the ileum, which contains receptor sites for the vitamin B12/intrinsic factor complex. Calcium ions are required for the reaction between ileal receptors and the intrinsic factor/vitamin B12 complex. The reaction is inhibited by EDTA and reduced by a pH below 5.4. The vitamin appears to be separated from intrinsic factor at the ileal receptor sites and is then bound to another protein carrier, transcobalamin II, which transports the vitamin and permits its uptake by a number of tissues. The subject has been well reviewed by Jacob and her colleagues (Jl). Removal of 60 cm of ileum may impair vitamin B12 absorption and with the loss of 180 cm absorption is almost always affected. 

The site of TC II synthesis has been the subject of much study and it has been shown that de novo synthesis occurs in the liver (E3,S7,T1), blood monocytes (R2,R3), and ileal enterocytes (C6,R4). Like intrinsic factor, TC II contains a single vitamin B12 binding site per molecule. However, unlike intrinsic factor, TC II will bind analogs of the vitamin (H6). A number of genetically determined variants of TC II have been described and were recognized by their altered electrophoretic mobility (D2,F3) and these are discussed in Section 8.1. 

Schilling, R. F., Clatanoff, D. V., and Korst, D. R., Intrinsic factor studies. III. Further observations utilizing the urinary radioactivity test in subjects with achlorhydria, pernicious anaemia or a total gastrectomy. J. Lab. Clin. Med. 45, 926-934 (1955). 

Estimates of requirements based on parenteral administration to subjects with pernicious anemia as a result of the lack of intrinsic factor (Section 10.9.2) are almost certainly erroneously high for subjects with normal enterohepatic circulation of the vitamin in pernicious anemia, the biliary vitamin B12 will not be reabsorbed to any significant extent, and requirements will therefore be considerably higher than normal. 

The absorption of vitamin B12 can be determined by the Schilling test. An oral dose of [ Co] or [ Co]vitamin B12 is given with a parenteral flushing dose of 1 mg of nonradioactive vitamin, and the urinary excretion of radioactivity is followed as an index of absorption of the oral material. Normal subjects excrete 16% to 45% of the radioactivity over 24 hours, whereas patients lacking intrinsic factor or with antiintrinsic factor antibodies excrete less than 5%. 

The daily loss is about 0.1% of the body pool in subjects with normal intrinsic factor secretion and enterohepatic circulation of the vitamin (Section 10.7.2). On this basis, the requirement is 0.3 to 1.8 nmol (1 to 2.5 /xg) per day (Herbert, 1987b). This is probably a considerable overestimate of requirements, because parenteral administration of less than 0.3 nmol per day is adequate to maintain normal hematology in patients with pernicious anemia, in whom the enterohepatic recycling of the vitamin is grossly impaired. 

The daily loss is about 0.1% of the body pool in subjects with normal intrinsic factor secretion turd enterohepatic circulation of the vitamin (Section... 

For detailed information on intrinsic factor (IF) the reader is referred to the recent monograph on this subject by the reviewer, the bibliography of which includes over 1500 references (G20). Therefore only the most salient points will be discussed here. 

The globalization of pharmaceutical research and development is expected to shorten the time required for product approval and registration, by increasing the number of subjects available for research studies and broadening an investigational product s exposure to ethnic intrinsic factors (genetic and physiological) and extrinsic factors (cultural and environmental). 

Intrinsic and Extrinsic Factors. We propose that the evolution of hormonal pheromones is affected by two fundamentally different factors intrinsic and extrinsic. Intrinsic factors are exclusively associated with interactions between or among conspecifics (i.e. intrinsic to a species pheromonal functions), and would include aspects such as the rate and mode of release of hormonal products by donors, and the sensitivity and specificity with which these products are detected by receivers. Thus, intrinsic factors are directly associated with the origins and continued existence of hormonal pheromones and are subject to evolutionary feedback as a consequence of their actions. 

Figure 2. A schematic representation of the influences of intrinsic factors on spying. The top fish in each pair is the donor, shown releasing an array of hormonal products (A-E). The bottom fish in each pair is the receiver. Above the receiver, a horizontal dashed line indicates no olfactory receptor is present for a hormonal product, a filled circle indicates a receptor is present, and an empty circle indicates an olfactory receptor has been recently expressed. Spying evolves when a receiver comes to detect a hormonal product (now termed a pheromonal cue) released by a conspecific donor and benefits from doing so. Most likely, the process starts with development of sensitivity to a single cue but may rapidly expand to include a mixture of compounds, the phenomenon we term, cue elaboration. Pheromonal mixtures will be subject to modification by extrinsic factors. Also they may come to serve a communicatory function (and thus be susceptible to a different suite of pressures) if the pheromone donor comes to benefit directly from releasing the cue.

Vitamin Bj2 deficiency is not generally related to a dietary lack. More often, this deficiency is due to specific disease processes, primarily the loss of intrinsic factor. Body stores of are large. If intake or absorption of the vitamin is abolished, it still takes from 1-2 yr to deplete the stores to the point where the serum Bj2 level falls below normal and from 2-6 yr before the full-blown syndrome develops. Since vitamin Bj2 is found in meat and dairy products, the only notable group with a dietary deficiency of this vitamin are strict vegetarians. Among healthy, elderly subjects, Bj2 absorption and stores are normal or only slightly lowered (Fairbanks and Elveback, 1983 McEvoy et al, 1982). Even in the poor elderly, Bj2 levels are normal (Bailey et al, 1980). 

Elderly people 40 subjects (19M) frequently suffering from vitamin B12 deficiency (>20%), often neither identified nor investigated because of its subclinical manifestations, or mainly caused by reduced production or lack of intrinsic factor (15-20%), or altered cobalamin absorption, or possibly associated with insufficient dietary intake. 

Vitamin B12 deficiency results more commonly from a stomach defect than from a dietary deficiency. Before it can be absorbed the vitamin B12 (extrinsic factor) that is released from associated peptides and proteins in the stomach must combine with the intrinsic factor, a small glycoprotein secreted by the parietal cells. Subjects who suffer from pernicious anaemia fail to produce intrinsic factor with the result that the vitamin is not absorbed and must be given by injection. Vitamin B]2 produced by microbes in the lower reaches of the intestine is of no use to the body. 

Baker and Mollin (to be published) also discovered some normal subjects who failed to absorb B normally unless they were given an injection of carbachol to stimulate the gastric secretion of intrinsic factor. In one of these patients the results of this test before carbachol stimulation were within the range found in patients with pernicious anemia. 

In testing intrinsic factor preparations unreliable subjects can be excluded and fecal excretion methods are satisfactory. The technique of Baker and Mollin (1955) is particularly suitable. With the use of a fixed dose of Co -labeled B12, two intrinsic factor preparations can be tested in parallel in successive weeks in the same patient over a range of doses wide enough to permit comparison of the absorption gradients obtained for each of the preparations (page 163). 

If it is true that there is an intestinal B12 acceptor akin to apoferritin (Glass et al., 1954), then in patients with pernicious anemia in relapse (the classical example of B12 deficiency), this acceptor should be quite unsaturated. If unsaturated, and if adequate amounts of intrinsic factor are supplied, it should be capable of accepting more B12 from the gut lumen than is accepted by the normal subject (Schilling, 1954). 

Hoff-j0rgensen (1952), Hoff-J0rgensen and Landboe-Christensen (1953), Hoff-J0rgensen et d. (1952), and Burkholder (1952) support this view, but there is considerable evidence against it. Fractions of gastric mucosa with the greatest binding activity had the least intrinsic factor activity (Prusoff et d., 1953 Everse et al., 1953). The subject is reviewed by Heinrich and Lahann (1954) and others. 

Foy and Kondi (1953) found that penicillin was effective in some megaloblastic anemias in Africans, but not in those who appeared to lack intrinsic factor. They suggest that the action was on the biosynthesis of hemopoietic factors. Small doses of an antibiotic may profoundly change the morphology (and presumably the metabolism) of microorganisms. For a discussion of the subject of antibiotics in nutrition, the reader is referred to Cuthbertson (1952). 

It is likely that only a very small part of this absorption is mediated by intrinsic factor. The gastric atrophy in pernicious anemia is very severe, and in the experience of Magnus and Ungley (1938 and unpublished) it is irreversible. Even if traces of intrinsic factor do persist, it is doubtful if they could account for all the absorption of B12 which occurs. Moreover, persons subjected to total gastrectomy, in whom no known source of intrinsic factor remains, can also absorb some part of an oral dose of radioactive vitamin B12— just as do patients with pernicious anemia (see page 189). Again, after oral doses of 3000 /tg. both normal persons and patients with pernicious anemia showed similar patterns of absorption and excretion, as judged by levels of vitamin B12 in serum and urine the presence or lack of intrinsic factor did not demonstrably influence the result. 

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