A 20-year-old woman comes to the clinic for evaluation of fatigue that has progressively worsened over the past month. The patient was recently diagnosed with celiac disease, but she has not strictly adhered to a gluten-free diet. Laboratory evaluation reveals macrocytic anemia with a low folate level but normal vitamin B12 level. Oral folic acid is prescribed. Which of the following biochemical changes is most likely to occur in this patient after starting treatment?
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Folate is a naturally occurring vitamin found in animal and plant products, most notably liver and leafy green vegetables; it is also fortified in many cereals and grains. Therefore, folate deficiency is rare in persons who consume a varied diet. However, deficiency can occur in the setting of increased cell turnover (eg, pregnancy, chronic hemolytic anemia), medications that interfere with folate metabolism (eg, methotrexate, antiseizure agents), and intestinal malabsorption. This patient with celiac disease, who is noncompliant with dietary restrictions, likely developed folate deficiency due to inflammation in the wall of the jejunum, which impaired folate absorption.
Folate has a crucial role in the generation of purines and pyrimidines by converting homocysteine to methionine. Specifically, 5-methyl-tetrahydrofolate donates its methyl group to vitamin B12, forming methylcobalamin, then methylcobalamin donates its methyl group to homocysteine to form methionine. In folate deficiency, homocysteine cannot be converted to methionine, leading to homocysteine accumulation (Choice C). In contrast, folate supplementation results in the rapid conversion of homocysteine to methionine, leading to low homocysteine and high methionine.
Methylmalonic acid is a biomarker for vitamin B12 because conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA requires vitamin B12. Because methylmalonyl-CoA mutase is not a folate-dependent enzyme, it is unaffected by changes in folate level.
(Choice B) Decreased homocysteine, increased methionine, and decreased methylmalonic acid would be expected after vitamin B12 supplementation, not folate supplementation.
(Choice D) Increased homocysteine, decreased methionine, and increased methylmalonic acid would be expected in vitamin B12 deficiency.
(Choice E) Isolated methylmalonic acidemia occurs in a rare autosomal recessive condition and is unrelated to folate deficiency and supplementation.
Educational objective:
Reduced forms of folate serve as methyl group donors in the synthesis of methionine. Folate deficiency leads to impaired methionine synthesis with accumulation of homocysteine, a precursor to methionine. Methylmalonic acid metabolism is unaffected by folate deficiency.