The Biological Principles of Disease
LLOYD H. SMITH, Jr., M.D.
Professor of Medicine; Associate Dean, University of California, San Francisco, School of Medicine, San Francisco. California
SAMUEL 0. THIER, M.D.
Sterling Professor and Chairman, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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INTERNATIONAL TEXTBOOK OF MEDICINE
A. H. SAMIY, M.D.
Professor of Clinical Medicine and Chief of
Division of Medicine, New York Hospital, Cornell Medical Center
New York, New York
LLOYD H. SMITH, JR., M.D.
Professor of Medicine; Associate Dean,
University of California, San Francisco, School of Medicine,
San Francisco, California
JAMES B. WYNGAARDEN, M.D.
Director, National Institutes of Health,
The Biological Principles of Disease
MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES
Volumes I and II of the International Textbook
have been conceived and written to follow a logical pedagogical approach
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CECIL TEXTBOOK OF MEDICINE.
Vitamin B12. In 1926,
Minot and Murphy observed that it was possible to treat pernicious anemia
by feeding raw liver. In 1929, Castle discovered that the intestinal absorption
of the anti-pernicious-anemia principle of liver, which he called extrinsic
factor (vitamin B12), depended on its first being bound to a factor secreted
by the gastric mucosa, which he called intrinsic factor. Further developments
included the identification of the chemical structure of vitamin B12 and
the elucidation of its mechanism of action.
Vitamin B12 is synthesized only in certain microorganisms. Animals depend on microbial synthesis for their vitamin B12 supply. Human foods that contain [high levels of] the vitamin are of animal origin (meat, liver, fish, eggs, and milk). The average daily diet in Western countries contains 5 to 30 ~g of vitamin B12, of which 1 to 5 ~g is absorbed. The total body stores of the vitamin in adults range from 2 to 5 mg, of which approximately 1 mg is found in the liver. The daily dietary requirement is about 2 to 3 p.g. Hence, after stopping intake of vitamin B12, or after total gastrectomy, it takes several years to deplete the body stores and for the symptoms of vitamin B12 deficiency to develop.
The structure of vitamin B12, or cyanocobalamin, was elucidated in 1955 by the x-ray crystallographic analysis of Dorothy Hodgkin. The vitamin B12 molecule (Fig. 16) consists of two main parts: (1) a planar group, a ring structure surrounding the cobalt atom, that resembles the porphyrin ring of heme except for a bond linking two pyrrole rings directly together instead of through a bridging carbon atom-this structure is called a corrin ring; and (2) a nucleotide group containing the base 5,6 dimethylbenzimidazolyl and phosphorylated ribose esterified with 1 amino, 2 propranol. Finally, a cyanide group is carried by the trivalent cobalt atom, which is also linked to the benzimidazole base. The term vitamin B,2 may be used to describe cyanocobalamin, although it is often used to include other forms of the vitamin in which the -ON is replaced by another side group. In nature, vitamin B12 exists largely as the two forms, methylcobalamin and 5’deoxyadenosylcobalamin. These are labile [easily changed] and are converted to a fourth form of vitamin B12, hydroxycobalamin. Both cyanocobalamin and hydroxycobalamin are used therapeutically.
*0.5 mg/dl bloodI24 hours.
Dietary vitamin B12 is released
from protein and peptide complexes in the stomach, where it attaches to
both intrinsic factor and a second vitamin B12 binding protein called R-binder.
Intrinsic factor is a glycoprotein that contains 15 per cent carbohydrate
and is secreted by the parietal cells of the body and the fundus of the
stomach. One molecule of intrinsic factor binds to one molecule of vitamin
B12 in the region of the edge of the corrin ring. The R-protein is degraded
by pancreatic secretions and the vitamin B12 released binds to further
intrinsic factor. This step is impaired in patients with pancreatic
disease, leading to reduced vitamin B12 absorption. The normal site
of absorption appears to be the distal ileum. It is possible to absorb
up to 1.5 pg of vitamin B12 from a single oral dose of intrinsic factor-vitamin
B12 complex. Following absorption, the ileum is reffactory [resistant]
to further vitamin B12 absorption for several hours. At a neutral pH and
in the presence of talcium ions, intrinsic factor-vitamin B12 complex passively
attaches to receptor sites on the brush borders of the ileal mucosa. It
then enters the mucosal cell, where it is found in the cytosol. After exit
from the ileal enterocyte, vitamin B12 is attached to a second major vitamin
B12 transport protein (transcobalamin II, see below) which is synthesized
in the ileal cells. Thereafter, the vitamin is transferred to the portal
blood, the peak blood level being reached only 8 to 12 hours after an oral
dose. Intrinsic factor does not enter the portal blood and its fate is
not absolutely clear. Only about 1 per cent of an oral dose of the order
of 30 to 300 p.g of vitamin B12 is absorbed in the absence of intrinsic
factor. This form of absorption occurs throughout the gut by simple passive
Vitamin B12 is transported on specific binding proteins called transcobalamins (TC), of which three forms, TOI, II, and III, have been isolated. TOII is the main delivery protein that transports cobalamins to tissues such as marrow and in the nervous system. It is synthesized by a variety of cells, including macrophages, ileal enterocytes, and the liver. The TOIlvitamin B12 complex attaches to a receptor site on the surface of various target cells and is internalized by pinocytosis. TOII is essential for vitamin uptake by cells, and in its absence a severe vitamin B12 deficiency state develops. The functions of TO’s I and III, which
are probably produced by leukocytes, are unknown.
The TO levels vary in a variety of disease states. As might be expected,
TOI levels rise markedly in various forms of granulocytic leukemia and
other myeloproliferative diseases and also during the leukocytosis
of infection. Increased TOII levels are observed in liver disease and pregnancy.
The metabolic functions of vitamin B12 are only understood in three well-defined reactions. One is the conversion of homocysteine to methionine, as shown in Figure 17. The enzyme involved is homocysteinemethionine methyl transferase, and the reaction requires 5-methyl tetrahydrofolate as a methyl donor, S. adenosylmethionine, and the reducing agent (FADH2) as well as methyl-B12 as a coenzyme. Vitamin B12-dependent methionine synthesis is important in the regeneration of tetrahydrofolate from methyltetrahydrofolate. The second reaction involving vitamin B12, as deoxyadenosylcobalamin, is the conversion of proprionate to succinate, as shown in Figure 18. This reaction is part of the route by which cholesterol and odd-chain fatty acids as well as a number of amino acids and thymine are used for energy requirements via the Krebs cycle. Patients with vitamin B12 deficiency may excrete excess methylmalonic acid. Finally, vitamin B22 is involved in the i~omerization of j3-leucine to ct-leucine; in vitamin B12 deficiency 13-leucine accumulates while ct-leucine is decreased. The interrelationships between vitamin B12 and folate metabolism in the synthesis of DNA are considered later-it is this function of vitamin B12 that undoubtedly accounts for the megaloblastic erythropoiesis and related phenomenon of abnormal DNA synthesis found in vitamin B12 deficiency states. Vitamin B12 is also essential for the function of metabolic pathways in the central nervous system.
FIgure 16. The structure of vitamin B12. (From Hoflbrand, A.V.: In Hardisty, R. M., and Weatherall, D. J. (eds.): Blood and Its Disorders. Oxford, Blackwell Scientific Publications, 1974.)
Odd chain fatty acids
H ATP, Mg, H~ CH3 CH2-COSCoA
t biotin I I 5’ deoxyadenosyl ~12
H3C-~ -COSCoA+ HcO3 - H3C-¶-COSCOA Mathylmalonyl H~lj~CoSCoA Methylmalonyl 2
H -CoA COOH CoA racamase COON CoA mutase COON
carboxylase L-rn.thylmalony/ - CoA s~iny/ - CoA
p~ionyI CoA D-niethylmalonyl - CoA
Figure 18. The metabolic interactions of propionyl OoA and succinyl OoA and the role of vitamin B12. (From
HofThrand, A. V.: In Blood and Its Disorders. Hardisty, R. M., and Weatherall, D. J. (eds.). Oxford, Blackwell Scientific Publications, 1974.)
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