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Within weeks of the development of early morphological abnormalities in the marrow, subtle changes appear in the peripheral blood (Eichner et al., 1971) when hypersegmentation of the neutrophils becomes apparent. The peripheral blood picture is variable before the development of a clearly increased mean cell volume or anemia (Lindenbaum et al., 1988). In some deficient individuals, macrocytes and macroovalocytes are seen on blood smears, but in others the erythrocytes may show only minimal anisocytosis or no abnormalities. When folate supply to the bone marrow becomes rate limiting for erythropoiesis, macrocytic cells are produced. However, because of the 120-day lifespan of normal erythrocytes, macrocytosis is not evident in the early stages of folate-deficient megaloblastosis.

As folate depletion progresses further, the mean cell volume increases above normal. Neutrophil hypersegmentation (defined as more than 5 percent five-lobed or any six-lobed cells per 100 granulocytes) is typically present in the peripheral blood at this stage of macrocytosis and the neutrophil lobe average is elevated.

Macrocytic anemia then develops, as first evidenced by a depression of the erythrocyte count. Eventually, all three measures of anemia (hematocrit, hemoglobin concentration, and erythrocyte concentration) are depressed. At this point, macroovalocytes and macrocytes are usually detectable in the peripheral blood, and hypersegmentation is more impressive (Lindenbaum et al., 1988).

Because the onset of anemia is usually gradual, compensating cardiopulmonary and biochemical mechanisms provide adaptive adjustments to the diminished oxygen-carrying capacity of the blood until anemia is moderate to severe. Symptoms of weakness, fatigue, difficulty concentrating, irritability, headache, palpitations, and shortness of breath therefore typically appear at an advanced stage of anemia. They may be seen at milder degrees of anemia in some patients, especially the elderly (Lindenbaum et al., 1988). Atrophic glossitis may also occur (Savage et al., 1994).

SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR FOLATE

The primary indicator selected to determine folate adequacy is erythrocyte folate, which reflects tissue folate stores, as described in detail below. For some life stage or gender groups, this is used in conjunction with plasma homocysteine (which reflects the extent of the conversion of homocysteine to methionine) and plasma or serum folate. Other indicators are discussed briefly below; risk reduc-



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