The notion that requirements for
folic acid may be higher in some tissues than others, resulting in localized deficiencies in spite of blood levels in the normal range was first suggested by the observation of megaloblastic changes in the cervical epithelium that responded to
folate supplementation. Theoretically, such deficiencies may arise from elevated
folate turnover in response to rapid tissue proliferation or repair; inactivation or alteration of its function by external agents such as tobacco, alcohol, or drugs; or altered metabolism or tissue uptake caused by an inborn error. Marginal dietary intake could aggravate these effects on cells at risk. Evidence for the possible existence of localized
folate deficiencies in the aerodigestive tract includes lower circulating
folate levels in smokers as compared with nonsmokers; yet lower circulating levels in smokers with bronchial
metaplasia; lower
folate levels in scrapings of the buccal mucosa of smokers than non-smokers; apparent improvement in bronchial atypical
metaplasia in smokers supplemented with
folic acid; lower erythrocyte
folate levels and higher prevalence of cellular features compatible with
folate deficiency in geographic areas and individuals in South Africa at high risk for
esophageal cancer; and a trend toward a lower prevalence of colonic dysplasia in
ulcerative colitis patients who use
folic acid supplements. These observations, as well as animal and in vitro studies, also suggest that
folate deficiency may be co-carcinogenic. Further research in this area will be aided by the development of animal models of localized
folate deficiency and of methodologies capable of measuring
folate levels in minute quantities of tissues and exfoliated cells.