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Variable response of bone marrow to feeding DL-5-formyltetrahydrofolate in pernicious anaemia
Abstract:
It has been suggested that the megaloblastic anaemia in pernicious anaemia is due to inadequate intracellular concentration of monoglutamyl folates other than methyltetrahydrofolate caused by diminished conversion of methyltetrahydrofolate to tetrahydrofolate (methylfolate trap). To test this, we have increased the concentration of methyltetrahydrofolate in the plasma of six patients with pernicious anaemia by feeding DL-5-formyltetrahydrofolate. The effect of therapy on bone marrow morphology and routine haematologic parameters was measured. Of two patients receiving 800 mug/d of DL-5-formyltetrahydrofolate, one had a significant response; of four receiving 6 mg/d, one converted erythroid maturation to normoblastic, and in two others some improvement was noted in levels of neutrophils, platelets or reticulocytes although marrow morphology remained megaloblastic. Response did not correlate with the degree of elevation of plasma folate. In patients receiving this therapy, slight increase of methylcobalamin in plasma may have occurred (P less than 0.05). These observations support ineffective utilization of methyltetrahydrofolate as the major cause of megaloblastic anaemia in pernicious anaemia, but indicate that the degree and location of block varied in different patients, and in different precursor cells of a single patient.
Insights
Pernicious anemia's megaloblastic anemia may stem from impaired methyltetrahydrofolate conversion. Supplementing with DL-5-formyltetrahydrofolate showed varied patient responses, suggesting a complex folate utilization issue.
Area of Science:
- Hematology
- Nutritional Biochemistry
- Medical Research
Background:
- Pernicious anemia is characterized by megaloblastic anemia.
- A proposed mechanism is the "methylfolate trap," where insufficient conversion of methyltetrahydrofolate to tetrahydrofolate leads to low intracellular monoglutamyl folate levels.
- This deficiency impacts DNA synthesis, causing megaloblastic changes.
Purpose of the Study:
- To investigate the "methylfolate trap" hypothesis in pernicious anemia.
- To determine if increasing plasma methyltetrahydrofolate levels with DL-5-formyltetrahydrofolate can correct megaloblastic anemia.
- To assess the impact of this intervention on bone marrow morphology and hematologic parameters.
Main Methods:
- Six patients with pernicious anemia were administered DL-5-formyltetrahydrofolate at two different dosages (800 µg/d and 6 mg/d).
- Bone marrow morphology and routine hematologic parameters (neutrophils, platelets, reticulocytes) were monitored.
- Plasma folate and methylcobalamin levels were measured to assess treatment efficacy and correlation.
Main Results:
- One of two patients receiving 800 µg/d showed a significant hematologic response.
- At 6 mg/d, one patient achieved normoblastic erythroid maturation, while two others showed partial improvement in peripheral blood counts.
- Hematologic response did not consistently correlate with elevated plasma folate levels.
- A slight, statistically significant increase in plasma methylcobalamin was observed in some patients.
Conclusions:
- The findings support the hypothesis that ineffective utilization of methyltetrahydrofolate contributes significantly to megaloblastic anemia in pernicious anemia.
- The data suggest variability in the "methylfolate trap" block among different patients and even within precursor cells of a single patient.
- DL-5-formyltetrahydrofolate administration can elicit partial or significant responses, indicating potential therapeutic avenues but highlighting the complexity of folate metabolism in this condition.