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vitamin B12 deficiency. First, numerous human case reports show onset or progression of neurological complications in vitamin B12-deficient individuals receiving supplemental folate (Table 8-12). Second, studies in monkeys (Agamanolis et al., 1976) and fruit bats (van der Westhuyzen and Metz, 1983; van der Westhuyzen et al., 1982) show that vitamin B12-deficient animals receiving supplemental folate develop signs of neuropathology earlier than do controls. The monkey studies used dietary methods to induce vitamin B12 deficiency whereas the fruit bat studies used a well-described method involving nitrous oxide (Metz and van der Westhuyzen, 1987). Third, a metabolic interaction between folate and vitamin B12 is well documented (Chanarin et al., 1989). Although the association between folate treatment and neurological damage observed in human case reports does not provide proof of causality, the hazard associated with excess supplemental folate cannot be ruled out. The hazard remains plausible given the findings from animal studies and the demonstrated biochemical interaction of the two nutrients. The resulting neurological damage may be serious, irreversible, and crippling.

For many years, it has been recognized that excessive intake of folate supplements may obscure or mask and potentially delay the diagnosis of vitamin B12 deficiency. Delayed diagnosis can result in an increased risk of progressive, unrecognized neurological damage. Evidence from animal as well as in vitro tissue and cell culture studies (Baxter et al., 1973; Hommes and Obbens, 1972; Kehl et al.,

TABLE 8-12 Dose and Duration of Oral Folate Administration and the Occurrence of Neurological Manifestations in Patients with Pernicious Anemia

Study

Number of Subjects

Dose (mg/d)

Duration

Occurrence of Neurological Manifestationsa

Crosby, 1960

1

0.35

2 y

1 of 1

Ellison, 1960

1

0.33–1

3 mo

1 of 1

Allen et al., 1990

3

0.4–1

3–18 mo

3 of 3

Baldwin and Dalessio, 1961

1

0.5

16 mo

1 of 1

Ross et al., 1948

4

1.25

9–23 mo

1 of 4

Chodos and Ross, 1951

4

1.25b

3.5–26 mo

3 of 4

Victor and Lear, 1956

2

1.5–2.55

10–39 mo

2 of 2

Conley and Krevans, 1951

1

4.5

3 y

1 of 1



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