Acquired Folate Deficiency

Folate deficiency, next to iron deficiency, is one of the most common micronutrient deficiencies worldwide. It is a component of malnutrition and starvation. Women are more frequently affected than men. Folate deficiency is common in mothers, particularly where poverty or malnutrition is prevalent, and dietary supplements are not provided. Folate stores are depleted after 3 months or sooner when the growing fetus and lactation impose increased demands for folate. The major benefit of folate sufficiency for the fetus is the prevention of neural tube defects. This is currently best achieved by administering folate (and cobalamin) to mothers during the pericon-ceptional period.

Table 4-6. Causes of Folic Acid Deficiency

I. Inadequate intake

A. Poverty, ignorance, faddism

B. Method of cooking (sustained boiling loses 40% folate)

D. Malnutrition (marasmus, kwashiorkor)

E. Special diets for phenylketonuria or maple syrup urine disease

F. Prematurity

G. Post-bone marrow transplantation (heat-sterilized food)

II. Defective absorption

A. Congenital, isolated defect of folate malabsorptiona

B. Acquired

1. Idiopathic steatorrhea

2. Tropical sprue

3. Partial or total gastrectomy

4. Multiple diverticula of small intestine

5. Jejunal resection

6. Regional ileitis

7. Whipple disease

8. Intestinal lymphoma

9. Broad-spectrum antibiotics

10. Drugs associated with impaired absorption and/or utilization of folic acid, e.g., diphenylhydantoin (Dilantin), primidone, barbiturates, oral contraceptive agents, cycloserine, metformin, ethanol, dietary amino acids (glycine, methionine)

11. Post-bone marrow transplantation (total body irradiation, drugs, intestinal GVH disease)

III. Increased requirements

A. Rapid growth (e.g., prematurity, pregnancy)

B. Chronic hemolytic anemia, especially with ineffective erythropoiesis (e.g., thalassemia major)

C. Dyserythropoietic anemias

D. Malignant disease (e.g., lymphoma, leukemia)

E. Hypermetabolic states (e.g., infection, hyperthyroidism)

F. Extensive skin disease (e.g., dermatitis herpetiformis, psoriasis, exfoliative dermatitis)

G. Cirrhosis

H. Post-bone marrow transplantation (bone marrow and epithelial cell regeneration)

Table 4-6. (Continued)

IV. Disorders of folic acid metabolism

A. Congenital6

1. Methylenetetrahydrofolate reductase (MTHFR) deficiency (OMIM 236250)

2. Glutamate formiminotransferase deficiency (OMIM 229100)

3. Functional N5-methyltetrahydrofolate:homocysteine methyltransferase deficiency caused by cblE (OMIM 236270) or cblG (OMIM 250940) disease

4. Dihydrofolate reductase deficiency (less well established)

5. Methenyl-tetrahydrofolate cyclohydrolase (less well established)

6. Primary methyl-tetrahydrofolate: homocysteine methyltransferase deficiency (less well established)

B. Acquired

1. Impaired utilization of folate a. Folate antagonists (drugs that are dihydrofolate reductase inhibitors, e.g., methotrexate, pyrimethamine, trimethoprim, pentamidine)

b. Vitamin B12 deficiency c. Alcoholism d. Liver disease (acute and chronic)

e. Other drugs (IIB10 above)

V. Increased excretion (e.g., chronic dialysis, vitamin B12 deficiency, liver disease, heart disease)

Abbreviation: OMIM, Online Mendelian Inheritance in Man (page 50).

aRare disorder. Isolated disorder of folate transport resulting in low CSF folate and mental retardation. The ability to absorb all other nutrients is normal. Defect is overcome by pharmacologic oral doses of folic acid or intramuscular folic acid (Lanzkowsky P, Erlandson, ME, Bezan AI. Isolated defect of folic acid absorption associated with mental retardation and cerebral calcifications, Blood 1969;34:452-65; Am J Med 1970;48:580-3).

bThese disorders are associated with megaloblastic anemia, mental retardation, disorders in gait, and both peripheral and central nervous system disease.

In addition, low daily folate intake is associated with a twofold increased risk for preterm delivery and low infant birth weight. These findings suggest that maternal folate status may affect birth outcome in ways other than neural tube defects.

Clinical folate deficiency is seldom present at birth. However, rapid growth in the first few weeks of life demands increased folate. There is a need for folate supplements at this time, particularly for premature infants, in doses of 0.05-0.2 mg/day.

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