Folate hematological effects

Raised methotrexate serum concentrations (over 100 nmol/1 at 36-42 hours after ingestion) are expected to increase the likelihood of several adverse effects, that is, gastrointestinal and hematological effects, but similar adverse effects can be found even with low methotrexate serum concentrations. Reduced red cell folate concentrations during methotrexate treatment also related to adverse effects and rises in liver enzjmes, and red cell folate concentrations above 800 nmol/1 protected against common adverse effects and treatment withdrawal (6). Several investigators now advocate the concomitant use of folic acid (5-7 mg/week and up to 27.5 mg/week) to reduce some of methotrexate-associated adverse effects without reducing its efficacy (7). 

Clinical implications of methionine synthase inhibition The inhibition of methionine synthase due to vitamin B12 deficiency induces megaloblastic anemia that is clinically indistinguishable from that caused by folate deficiency. The hematological effect in both cases results in levels of 5,10-methyleneTHF that are inadequate to sustain thymidylate biosynthesis. Clinically, it is essential to ascertain whether the anemia is the result of folate deficiency or vitamin Bi2 deficiency by differential diagnostic techniques. Vitamin B12 is essential for the synthesis of myelin in nerve tissue, a function probably related to... 

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. 

In a meta-analysis of 307 patients with rheumatoid arthritis from seven randomized clinical trials, of whom 147 took folate supplementation, hematological adverse effects were not significantly reduced in the folate group (8). However, there was a 79% reduction in mucosal and gastrointestinal adverse effects in patients taking folic acid and a non-significant trend toward a reduction (42%) in patients taking folinic acid. Disease activity was not modified by low doses of folate. Finally, the authors noted that folinic acid is more expensive. 

Most hematological adverse effects associated with trimethoprim have been reported with co-trimoxazole. These include macrocytic and megaloblastic anemia, aplastic anemia, neutropenia, hypersegmentation of leukocytes, thrombocytopenia, and pancytopenia (12,61-63,75-79). Sulfonamides alone have not been associated with folate deficiency, but in combination with trimethoprim they can deplete folate stores in patients with preexisting deficiency of folate or vitamin B12 (80). Treatment with co-trimoxazole can impair the function of mobilized autologous peripheral blood stem cells (81). 

Treatment of the folate-deficient patient with folic acid permits the early eryth-roblast to divide, producing late erythroblasts and, eventually, reticulocytes and red blood cells. These effects can very easily be detected by examining blood samples taken before and after the injection and determining the percentage of reticulocytes. Normally, the concentration of reticulocytes in the bloodstream is quite low. A burst in the nrunber can be induced by injecting folic acid (0.1 mg) into a folate-deficient patient. It should be pointed out that injecting vitamin B 2 into a Bi2-deficient patient, or folate into some Bi2-deficient patients, can also cause this burst. Thus, the hematological response to vitamin injections is not a reliable indicator of which vitamin deficiency was present. 

---