Cobalamin Vitamin B12 and Folic Acid Deficiency

A deficiency of vitamin B12 or folic acid may be suspected when a macrocytic anemia (MCV >100 fL) is present. Vitamin B12 and folate deficiency causes a megaloblastic anemia, which is one type of macrocytic anemia.

The hematologic picture is identical for both folate and vitamin B12 deficiency. Megaloblasts are enlarged blastic cells (precursors to the erythroid and myeloid cell lines) found in the bone marrow and caused by aberrant DNA synthesis. The peripheral blood smear typically shows the presence of oval macrocytes, hypersegmented neutrophils (>5% neutrophils with 5 lobes or any neutrophil with 6 lobes). Anisocytosis (size variation) and poikilocytosis (shape variation) of the red blood cells (RBCs) are often present, so the RBC distribution width (RDW) is increased. The reticulocyte count is usually decreased. Thrombocytopenia is present in 12% and leukope-nia in 9% of cases; occasionally, B12 or folate deficiency will present with pancytopenia. Coexisting disease such as iron deficiency, inflammatory process, renal failure, or thalassemia trait also may normalize the mean corpuscular volume (MCV) value in the patient with vitamin B12 or folate deficiency.

The clinician must distinguish folate from B12 deficiency, because supplementing one will not correct the symptoms from deficiency of the other, i.e., folate replacement will not improve the neuropsychiatric abnormalities caused by vitamin B12 deficiency. The neurologic signs and symptoms, such as paresthesias, memory loss, dementia, and weakness, may precede hematologic abnormalities. Vitamin B12 and folate deficiency often coexist because some causes overlap (Table 15-11).

Because vitamin B12 is a cofactor in the conversion of methylmalonic acid to succinyl coenzyme A (CoA) and homocysteine to methionine, deficiencies of vitamin B12 will lead to increased levels of methylmalonic acid and homocys-teine. Folate is required in the conversion of homocysteine to methionine, but not in the conversion of methylmalonic acid to succinyl CoA. Folate deficiency is associated with elevated homocysteine, but not methylmalonic acid. The reference range for vitamin B12 is often listed as 200 to 900 pg/mL;

however, it is now recognized that a significant portion of patients with vitamin B12 levels of 200 to 400 pg/mL have symptoms of vitamin B12 deficiency.

Folate levels greater than 4 ng/mL are considered normal; levels of 2 to 4 ng/mL are indeterminate. A person in negative folate balance will become serum deficient before tissue folate stores decrease; therefore a low serum folate level indicates a negative folate balance, but not necessarily tissue folate deficiency. Intake of folate may normalize serum levels initially, so serum folate levels should be determined before a hospitalized or potentially deficient patient is fed, takes vitamins, or is given a transfusion. Measuring RBC folate levels is not recommended because it is difficult to interpret. Instead, testing for methylmalonic acid and homocysteine can help determine if patients with levels in the low-normal range actually have vitamin B12 or folate deficiency. Folic acid is absorbed in the upper small bowel, whereas B12 is absorbed mainly in the ileum with the help of intrinsic factor, which is secreted by the gastric parietal cells. Nutritional factors and malabsorption syndromes are principal reasons for deficiency of both vitamin B12 and folic acid. Hemolysis will falsely elevate serum folic acid levels.

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