Folates and Cobalamins

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Information on current clinical trials is posted on the Internet at www. All studies receiving U. Berkow R. The Merck Manual-Home Edition. McGraw-Hill Companies. New York, NY; Bennett JC, Plum F. Cecil Textbook of Medicine.

Philadelphia, PA: W. Saunders Co; Megaloblastic anemia and other causes of macrocytosis. Clin Med Res. Management, prevention and control of megaloblastic anemia, secondary to folic acid deficiency. Nutr Hosp. Ward PC. Modern approaches to the investigation of vitamin B12 deficiency.

Anemia, Megaloblastic - NORD (National Organization for Rare Disorders)

Clin Lab Med. Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry.

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Thiamine responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Blood Cells Mol Dis. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol. Wickramasinghe SN. The wide spectrum and unresolved issues of megaloblastic anemia.

McKusick VA.

Does this test have other names?

The content of the website and databases of the National Organization for Rare Disorders NORD is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. About News Events Contact. General Discussion Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells megaloblasts.

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Causes The most common causes of megaloblastic anemia are deficiency of either cobalamin vitamin B12 or folate vitamin B9. In some cases, the cause of megaloblastic anemia is unknown idiopathic. Affected Populations Megaloblastic anemia affects males and females in equal numbers. Related Disorders Symptoms of the following disorders can be similar to those of megaloblastic anemia.

Diagnosis A diagnosis of megaloblastic anemia is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of blood tests.

Standard Therapies Treatment The treatment of megaloblastic anemia depends upon the underlying cause of the disorder. Investigational Therapies Information on current clinical trials is posted on the Internet at www. Davis TH. Megaloblastic Anemia.

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Emedicine Journal, January 29, Methods by which cobalamin deficiency decreases intracellular folate levels. Methyltetrahydrofolate MeFH 4 , the principal form of folate in the bloodstream, circulates in the unconjugated form i. This and other forms of unconjugated FH 4 can be taken into cells but leak out again unless they are conjugated. MeFH 4 is not a substrate for the conjugating enzyme, so conjugation cannot occur until the MeFH 4 is converted to another form of folate.

Cobalamin is necessary for this process because it is the cofactor for the reaction that converts MeFH 4 to FH 4. Newly transported folate remains in the form of MeFH 4 , which cannot be conjugated and leaks back out of the cell. According to the methylfolate trap hypothesis , all forms of FH 4 other than MeFH 4 can be conjugated, so MeFH 4 is the only folate species that leaks out of the cell.

Homocys met, homocysteine methyltransferase. The methylfolate trap hypothesis 75 is based on the fact that the folate-requiring enzyme N 5 -methyltetrahydrofolate—homocysteine methyltransferase is also dependent on cobalamin.

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The hypothesis states that in cobalamin deficiency tissue folates are gradually diverted into the N 5 -methyltetrahydrofolate pool because of slowing of the methyltransferase reaction, 76 the only route out of that pool for folate. As N 5 -methyltetrahydrofolate levels increase, the levels of other forms of folate decline, with a consequent fall in the rates of reactions in which those forms participate.

In its simplest form, the hypothesis predicts that in cobalamin deficiency tissue levels of N 5 -methyltetrahydrofolate are abnormally high and those of other forms of folate are abnormally low. Although serum N 5 -methyltetrahydrofolate levels are frequently elevated in cobalamin deficiency, 77 tissue folate levels, predominantly polyglutamates, decline. Thus, although sequestration of tissue folates in an expanded N 5 -methyltetrahydrofolate pool may account for some of the effects of the blockade in methyltransferase activity, the major problem seems to be a failure to convert newly acquired folate into a form that can be retained by the cell.

The upshot is development of tissue folate deficiency as the unconjugated folate leaks out see Fig. The whole process is aggravated by a drop in tissue levels of SAMe as the methionine supply is curtailed because of the diminished activity of the methyltransferase. The relief of this inhibition as SAMe levels fall accelerates the flow of folates toward N 5 -methyltetrahydrofolate, further aggravating the metabolic imbalance resulting from impairment in methyltransferase activity.

This problem could be overcome if N 5 -methyltetrahydrofolate were converted into a substrate for the conjugating enzyme by another route. In theory, this could be accomplished by reversal of the N 5 , N 10 -methylene FH 4 reductase reaction. For practical purposes, however, the N 5 , N 10 -methylene FH 4 reductase reaction is irreversible in vivo.

This hypothesis holds that formate starvation is the basis for folate-responsive megaloblastic anemia of cobalamin deficiency. Intrinsic factor is one of a number of binding proteins in which cobalamin is ensconced as it makes its way through the body Table 41—2. Intrinsic factor is needed for the absorption of cobalamins taken orally at physiologic dosage levels. Human intrinsic factor is a glycoprotein Mr approximately 44, encoded by a gene on chromosome This specificity allows for the exclusion of other noncobalamin corrinoids during the tightly regulated absorptive process.

In humans, intrinsic factor is synthesized and secreted by the parietal cells of the cardiac and fundic mucosa. It is enhanced by the presence of food in the stomach, vagal stimulation, histamine, and gastrin. Gastric juice also contains other cobalamin-binding glycoproteins. Elucidation of the primary protein structure of the R proteins reveals that they belong to the same family of isoproteins as the plasma haptocorrin HC binder previously known as transcobalamins I and III. These HC-like proteins are produced mainly by the salivary glands.

Cobalamins in foods are liberated in the stomach by peptic digestion.

Vitamin B12 and folate

The intrinsic factor—cobalamin complex, which is very resistant to digestion, 91 traverses the intestine until it reaches the intrinsic factor receptor, cubilin , 92 a kDa peripheral membrane glycoprotein located in the microvillus pits of the ileal mucosa brush-border. Cubilin forms part of a multifunctional epithelial receptor complex also found in the yolk sac and renal proximal tubule cells.

Mutations affecting either of the two proteins disrupt the normal process of the intestinal phase of cobalamin absorption. In addition to the tightly embracing components of the CUBAM complex, a distinct large multifunctional protein, megalin, which belongs to the low-density lipoprotein family, 96 also participates in the conformational changes that accompany internalization. The intrinsic factor—cobalamin receptor complex is taken into the ileal mucosal cells over 30 to 60 minutes by endocytosis, 99 where the vitamin is processed and released into the portal blood over many hours.

The receptors recycle to the microvillus surface to shuttle another load of intrinsic factor—cobalamin complex. During its sojourn in the ileal enterocyte, the vitamin first appears in the lysosomes, but by 4 hours most of the vitamin is located in the cytosol. Cobalamin from a small oral dose 10 to 20 mcg starts to appear in the blood after 3 to 4 hours, and the vitamin reaches a peak level in 6 to 12 hours.

In the portal blood, the cobalamin is complexed with a cobalamin-transporting protein known as transcobalamin TC previously known as TC II. Like the folates, the cobalamins undergo appreciable enterohepatic recycling. The cobalamin is released by digestion of the HC by pancreatic proteases, and then is taken up by intrinsic factor and reabsorbed.

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