Serum folates

Macrocytic anemias are characterized by increased mean corpuscular volume (110 to 140 fL). One of the earliest and most specific indications of macrocytic anemia is hypersegmented polymorphonuclear leukocytes on the peripheral blood smear. Vitamin B12 and folate concentrations can be measured to differentiate between the two deficiency anemias. A vitamin B12 value of less than 150 pg/mL, together with appropriate peripheral smear and clinical symptoms, is diagnostic of vitamin B12-deficiency anemia. A decreased RBC folate concentration (less than 150 ng/mL) appears to be a better indicator of folate-deficiency anemia than a decreased serum folate concentration (less than 3 ng/mL). 

Impaired glucose tolerance decreased pregnanediol excretion reduced response to metyrapone test reduced serum folate concentration. 

Serum folate levels Serum folate levels may be depressed by therapy. 

Drug/Lab test interactions Therapeutic levels of rifampin inhibit standard assays for serum folate and vitamin 612-... 

Serum folate, vitamin D (if on long-term therapy)... 

CBC serum folate concentrations <0.005 mcg/ml indicate folic acid deficiency and concentrations <0.002 mcg/ml usually result in megaloblastic anemia... 

Periodic CBC, liver and renal function tests, serum folate, vitamin D during prolonged therapy... 

Hatzis, C. M., Bertsias, G. K., Linardakis, M., Seott, J. M., Kafatos, A. G. (2006). Dietary and other lifestyle eorrelates of serum folate eoneentrations in a healthy adult population in Crete, Greeee a eross-seetionial study. Nutr. /., 5, 5. 

Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes. A dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients. Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy. Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis. 

Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikian V (1977) Serum folates in man. J Clin Pathol 30 438-448... 

Metformin can cause reduced vitamin Bi2 absorption, reducing serum Bi2 concentrations and causing megaloblastic anemia (87), the prevalence of which was 9% in 600 patients with type 2 diabetes taking biguanides (phen-formin or metformin) for a mean of 12 years (88). In 353 patients with type 2 diabetes, treated with insulin, who took metformin for 16 weeks in a placebo-controlled study, metformin increased serum homocysteine concentrations by 4% and reduced serum folate by 7% and vitamin Bi2 by 14% (89). 

A 63-year-old man with type 2 diabetes, who had taken metformin for at least 5 years, had a low serum vitamin Bi2 concentration (110 pg/ml reference range 200-230) and a normal serum folate (90). There were no autoantibodies. A Schilling test showed malabsorption of vitamin Bi2. Metformin was withdrawn and 2 months later a Schilling test showed no malabsorption. 

This case prompted a report of 10 metformin- associated patients with cobalamin deficiency among 162 patients with vitamin Bi2 concentrations below 200 pg/ml (91). They had taken a mean dose of metformin of 2015 mg/ day for an average of 8.9 years. The mean vitamin B12 concentration was 140 pg/ml. All had normal serum folate and creatinine concentrations and no antibodies to intrinsic factor. In one patient there was malabsorption. 

Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency (see above). However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency. In patients with megaloblastic anemia, folate status is assessed with assays for serum folate or for red blood cell folate. Red blood cell folate levels are often of greater diagnostic value than serum levels, since serum folate levels tend to be quite labile and do not necessarily reflect tissue levels. 

Gambichler, T. etal., Serum folate levels after UVA exposure a two-group parallel randomized controlled trial, BMC Dermatol., 1, 8, 2001. 

M6. Martin, J. D., Davis, R. E., and Stenhouse, N., Serum folate and vitamin B12 levels in pregnancy with particular reference to uterine bleeding and bacteriuria. J. Obstet. Gynaecol. Br. Commonw. 74, 697-701 (1967). 

A 6-month-old child was breast-fed exclusively by a mother who had been a strict vegetarian for at least 7 years. He was totally unresponsive to stimuli. His hemoglobin was 5.7 g/dL, and his bone marrow aspirates showed megaloblastic changes in blood cells. His serum folate and iron were normal. His urine contained increased amounts of homocystine, methylmalonic acid, and glycine. Propose a reason for this infant s illness, and discuss its biochemical etiology. Discuss other possible reasons for the same or similar symptoms in a patient. Explain the abnormal serum and urine chemistries. 

Carney MW. 1967. Serum folate values in 423 psychiatric patients. Br Med J 4 512-516. 

There is considerable enterohepatic circulation of folate, equivalent to about one-third of the dietary intake. Methyl-tetrahydrofolate is secreted in the bUe, then reabsorbed in the jejunum together with food folates. In experimental animals, bUe drainage for 6 hours results in a reduction of serum folate to 30% to 40% of normal (Steinberg et al., 1979). There is very litde loss of folate jejunal absorption is very efficient, and the fecal excretion of 450 nmol (200 /xg) of folates per day largely represents synthesis by intestinal flora and does not reflect intake to any significant extent. 

Serum folate below 7 nmol per L or erythrocyte folate below 320 nmol per L indicates negative folate balance and early depletion of body reserves. At this stage, the first bone marrow changes are detectable. 

About30% ofvitamin Bi2-deficient subjects have elevated serum folate. This is mainly methyl-tetrahydrofolate, the result of the methyl folate trap (Section 10.3.4.1). About one-third of folate-deficient subjects have low serum vitamin B12 the reason for this is not clear, but it responds to the administration of folate supplements. 

About30% of vitaminBi2-deficient subjects have elevated serum folate. This is mednly methyl-tetrahydrofolate, the result of the methyl folate trap (Section... 

Vitamin B12 deficiency can also cause megaloblastic anemia. White-centered hemorrhages can occur in the posterior pole, and disc pallor also may be seen. If the anemia is severe, cotton-wool spots may appear. A complete blood count can confirm that megaloblastic anemia exists. Serum folate and vitamin B12 levels should be determined and appropriate therapy (intramuscular injections of hydroxocobalamin) should be instituted at the earliest sign of megaloblastic anemia. 

Three forms of folate appear to be transported in the blood foHc acid, folate loosely bound to low affinity binder serum proteins (such as albumin, OC-macroglobulin, and transferrin), and folate bound to high affinity protein binders. Approximately 5% of total serum folate is being transported by high... 

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