Folate, absorption deficiency

Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. 

Several drugs (e.g., sulfasalazine, trimethoprim-sulfamethoxazole, and methotrexate) have been reported to cause a fohc acid deficiency megaloblastic anemia. These drugs either interfere with folate absorption or inhibit the dihydrofolate reductase enzyme necessary for conversion of dihydrofolate to its active tetrahydrofolate form (see Chap. 102, on drug-induced blood dyscrasias). 

These authors previously found (S12) that in all of 16 women who initially had subnormal serum folate concentrations, serum folate concentrations rose within 3 months after OCAs were stopped. Subsequently they reported (SIO) 3 women with low serum folate levels while taking OCAs and low folate polyglutamate absorption that persisted after medication was discontinued. It was of interest that one of these subjects developed gluten-sensitive enteropathy a year later and a second had a family history of that disease. Other case reports of folate deficiency and mild intestinal malabsorption in users of OCAs have appeared (J3, T2, W12). It should be emphasized, therefore, that evidence of impaired folate absorption in women taking these agents may suggest the presence of inapparent small bowel disease. 

Folate deficiency is most likely to occur in patients on long-lasting AED therapy. Furthermore, folate concentrations are inversely related to the number of prescribed AEDs. Patients on combinations of two or more AEDs tend to have lower folate levels than patients on monotherapy. Combinations of AEDs may have synergistic effects on folate absorption and/or metabolism. Moreover, the dietary intake of B vitamins tends to decrease with an increasing number of AEDs. Patients on combination therapy tend to a have more severe epilepsy, often associated with other neurological deficits and may even need to live in institutions. 

About 80% of dietary folate is in the form of polyglutamates a variable amount may be replaced by various one-carbon fragments or be present as dihydrofolate derivatives. Folate conjugates are hydrolysed in the small intestine by conjugase (pteroyl-polyglutamate hydrolase), a zinc-dependent enzyme of the pancreatic juice, bile and mucosal brush border zinc deficiency can impair folate absorption. Free folate, released by conjugase action, is absorbed by active transport in the jejunum. 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

Deficiency of folic acid Decreased intake, defective absorption, or increased demand (eg, in pregnancy) for folate... 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

Since sulfasalazine inhibits the absorption of folic acid, patients may become folate deficient during longterm therapy. Sulfasalazine decreases the bioavailabiUty of digoxin. Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy. 

Severe cyanocobalamin (vitamin B12) deficiency results in pernicious anemia that is characterized by megaloblastic anemia and neuropathies. The symptoms of this deficiency can be masked by high intake of folate. Vitamin B12 is recycled by an effective enterohep-atic circulation and thus has a very long half-hfe. Absorption of vitamin B12 from the gastrointestinal tract requires the presence of gastric intrinsic factor. This factor binds to the vitamin, forming a complex that... 

Both sequential and non-sequential types of oral contraceptives impair the absorption of polyglutamic folate but not that of monoglutamic folate the change can result in megaloblastic anemia in predisposed subjects, for example those with celiac disease or having a deficient diet (182). 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

There is considerable evidence that rapidly growing neoplastic tissue consumes folate at so rapid a rate that folate deficiency megaloblastosis can occur in the host cells (14, 15). There is also evidence that vitamin B-12 deficiency may slow tumor growth, whether that deficiency results from inadequate absorption or elevated levels in serum of a vitamin B-12 binder which does not deliver the vitamin to tumor tissue (16), but will deliver it to the liver in a calcium-dependent fashion (14,... 

The gastritis and chronic pancreatitis associated with chronic alcoholism may result in a reduction of the amount of vitamin B12 absorbed but this has not been found to result in a clinical deficiency (M4). Alcohol can also cause damage to the ileum. Lindenbaum and Lieber gave alcohol to human volunteers for periods of 13—37 days and found that absorption of the vitamin was impaired in six of eight volunteers and this was not corrected by the addition of intrinsic factor or pancreatin (L10,L11). Biopsy of the ileum showed ultra-structural evidence of mitochondrial damage (Rll). It has been shown previously that folate deficiency may result in a reduction in the serum vitamin B12 level (H16) and the low serum vitamin B12 levels found in some alcoholics is probably secondary to folate depletion, which is common in this condition (L12). How folate is able to influence the serum vitamin B12 level is not clear. 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

Antibiotics. Long-term administration of antibiotics could lead to vitamin B6 deficiency, If symptoms of peripheral neuropathy develop (numbness and tingling of the extremities), administer vitamin B6. Sulfasalazine can decrease the absorption of folic acid, and trimethoprim can cause folate deficiency, hence the need to administer folic acid if there is evidence of deficiency. Rifampicin can cause disturbances in vitamin D metabolism and lead to osteomalacia. The absorption of tetracyclines can be reduced by calcium, magnesium, iron and zinc, while this antibiotic could also decrease the absorption of these minerals. This effect is probably least with minocycline and is not confirmed with doxycycline. Doses of minerals and antibiotic should be separated by at least 2 hours. The absorption of quinolones is reduced by cationic and anionic supplements. 

Because conjugase is a zinc metallo-enzyme, zinc deficiency can impair the absorption of conjugated food folates, but not folate monoglutamate. 

Folate deficiency is relatively common 8% to 10% of the population of developed countries have low or marginal folate stores. By contrast, dietary deficiency of vitamin B12 is rare, and deficiency is most often the result of impaired absorption (Section 10.7.1). 

The predominant causes of folate deficiency in non-alcoholics are impaired absorption or metabolism or an increased demand for the vitamin. 

A minority of alcoholics develop nutrient deficiencies. In Western countries, alcoholics represcrit the largest population segment that can benefit from dietary intervention. Alcoholics are at risk for deficiencies in folate, thiamin, riboflavin, vitamin B, vitamin A, and magnesium, particularly when the intake of these substances is low. In some cases, absorption of the nutrient is impaired in others, catabolism of the nutrient is iitcreased. Thiamin deficiency is a firmly established consequence of alcoholism, as discussed in the iTiiamin section. 

Chronic alcoholism is the major cause of folate deficiency in the United States. Alcoholics generally have poor diets — for example, one liter of whiskey per day. It is not dear if the alcohol induces metabolic defects that interfere with the metabolism and function of folate. Beer docs contain folate, as this product is brewed with yeast, an organism containing high levels tif the vitamin. Wine and hard liquors, on the other hand, contain little or no folate. The elderly may also be at risk for folate deficiency. It is thought that in the elderly the deficiency is due to poor diets rather than age-related defects in the absorption and utilization of folate. 

Vtamin A supplementation, 564-565 Vitamin B(, 493, 541-542 aminotranK/ei ase, 209 assessmenl of status, 546-550 biochcinistry, 542-545 cardiovascular disease and, 553 homocysteine and, 550-554 homocysbnuria, 550,554 toxidty, 550 water solubility, 27 Vitamin Bs deficiency, 545-546 Vitamin supplements, 551 Vitamin Bu, 493,507, 516 absorption, 81-82 assessment of status, 522-524 biocbemistry, 516-517 chemical structure, 517 Cobalt and, 4t homocystBine and, 553 Vitamin Bij dehdency, 517-524 causes of, 518-522 elderly population, 521,553 folate deficiency and, 507, 511-312, 518 hematologic signs, 513... 

Sulfonamides are not directly associated with folate deficiency and megaloblastic anemias. Sulfasalazine can affect the absorption of folates, but inflammatory bowel... 

---