Chapter 100. Megaloblastic Anemias (Part 3)

Most foods contain some folate. The highest concentrations are found in liver, yeast, spinach, other greens, and nuts (100 µg/100 g). The total folate content of an average Western diet is ~250 µg daily, but the amount varies widely according to the type of food eaten and the method of cooking. Folate is easily destroyed by heating, particularly in large volumes of water. Total-body folate in the adult is ~10 mg, the liver containing the largest store. Daily adult requirements are ~100 µg, so stores are only sufficient for 3–4 months in normal adults and severe folate deficiency may...
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Chapter 100. Megaloblastic Anemias (Part 3) Chapter 100. Megaloblastic Anemias (Part 3) Most foods contain some folate. The highest concentrations are found inliver, yeast, spinach, other greens, and nuts (>100 µg/100 g). The total folatecontent of an average Western diet is ~250 µg daily, but the amount varies widelyaccording to the type of food eaten and the method of cooking. Folate is easilydestroyed by heating, particularly in large volumes of water. Total-body folate inthe adult is ~10 mg, the liver containing the largest store. Daily adult requirementsare ~100 µg, so stores are only sufficient for 3–4 months in normal adults andsevere folate deficiency may develop rapidly. Absorption Folates are absorbed rapidly from the upper small intestine. The absorptionof folate polyglutamates is less efficient than for monoglutamates; on average,~50% of food folate is absorbed. Polyglutamate forms are hydrolysed to themonoglutamate derivatives, either in the lumen of the intestine or within themucosa. All dietary folates are converted to 5-methylTHF (5-MTHF) within thesmall-intestinal mucosa before entering portal plasma. The monoglutamates areactively transported across the enterocyte by a carrier-mediated mechanism.Pteroylglutamic acid at doses >400 µg is absorbed largely unchanged andconverted to natural folates in the liver. Lower doses are converted to 5-MTHFduring absorption through the intestine. About 60–90 µg of folate enters the bile each day and is excreted into thesmall intestine. Loss of this folate, together with the folate of sloughed intestinalcells, accelerates the speed with which folate deficiency develops in malabsorptionconditions. Transport Folate is transported in plasma; about one-third is loosely bound to albuminand two-thirds unbound. In all body fluids (plasma, cerebrospinal fluid, milk, bile)folate is largely, if not entirely, 5-MTHF in the monoglutamate form. Two types offolate-binding protein are involved in entry of MTHF into cells. A high-affinityfolate receptor takes folate into cells by endocytosis, is internalized by clathrin-coated pits or in a vesicle (caveola), which is then acidified, releasing folate.Folate is then carried by the membrane folate transporter into the cytoplasm. Thehigh-affinity receptor is attached to the outer surface of the cell membrane byglycosyl phosphatidylinositol linkages. It may be involved in transport of oxidizedfolates and folate breakdown products to the liver for excretion in bile. Anindependent low-affinity reduced-folate carrier also mediates uptake ofphysiologic folates into cells but also of methotrexate. Biochemical Functions Folates (as the intracellular polyglutamate derivatives) act as coenzymes inthe transfer of single-carbon units (Fig. 100-1 and Table 100-2). Two of thesereactions are involved in purine and one in pyrimidine synthesis necessary forDNA and RNA replication. Folate is also a coenzyme for methionine synthesis, inwhich methylcobalamin is also involved and in which THF is regenerated. THF isthe acceptor of single carbon units newly entering the active pool via conversionof serine to glycine. Methionine, the other product of the methionine synthasereaction, is the precursor for S-adenosylmethionine (SAM), the universal methyldonor involved in >100 methyltransferase reactions (Fig. 100-1). Figure 100-1 The role of folates in DNA synthesis and in formation on S-adenosylmethionine (SAM), which is involved in numerous methylation reactions.[Reprinted from Hoffbrand AV et al (eds), Postgraduate Haematology, 5th ed,Blackwell Publishing, Oxford, UK 2005; with permission.] During thymidylate synthesis, 5,10-methylene-THF is oxidized to DHF(dihydrofolate). The enzyme DHF reductase converts this to THF. The drugsmethotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim inhibit DHFreductase and so prevent formation of active THF coenzymes from DHF. A smallfraction of the folate coenzyme is not recycled during thymidylate synthesis but isdegraded.