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Folate & B12 Deficiency, Megaloblastic Anemia

Vitamin B9 (Folate/Folic Acid) is very important for 1 carbon chemical reactions (AKA methylation) during the creation of DNA. These functions are particularly important in tissues that undergo frequent cellular division (like hematopoietic cells) and during periods of rapid cellular division (such as infancy and pregnancy). Folate is found naturally in leafy vegetables and Folium is the Latin word for leaf. Today many grains are also fortified with Folate. With so many items having Folate added a deficiency from decreased intake of Folate is not very common. Usually a deficiency is caused by an increased demand for folate through pregnancy or hemolytic anemias such as Sickle Cell Disease. Folate deficiencies in pregnant women are linked with the occurrence of Neural Tube Defects in the fetus. A deficiency can also be caused by drugs that inhibit the pathways that Folate is involved in such as Trimethoprim (antibiotic) and Methotrexate (Chemotherapy).

A Folate deficiency primarily causes anemia (decreased red blood cells). Anemias can present with a wide range of symptoms including weakness, fatigue, pale skin and shortness of breath. Folate Deficiency causes a specific type of Anemia called Macrocytic/Megaloblstic Anemia where the size (Mean Corpuscular Volume) of the red blood cells increased. This is because as the creation of DNA is inhibited the cell cycle in the hematopoietic cells is stalled. Cellular division is stopped but the cell continues to grow resulting in a smaller number of cells which are larger than normal cells. Patients with this type of anemia also often present with Hypersegmented Neutrophils on a blood smear, which is a neutrophil with 5 or more “segments” in the nucleus.

You are also going to see an elevation of Homocysteine levels in Folate Deficiency. This is because B12 needs to receive a methyl group from Folate so it can pass it on to Homocysteine to create Methionine. Less Folate means B12 doesn’t have a methyl group to pass on and Homocysteine builds up. Unlike B12 deficiencies, Folate deficiency does not result in a buildup of Methylmalonic Acid or neurological symptoms.

Vitamin B12 (Cobalamin) is a vitamin, like Folate, that is important for 1 carbon chemical reactions. B12 is found in many animal products and Vegans are at the highest risk of deficiency. B12 taken in through the diet is bound to proteins. Stomach acid and digestive enzymes must first separate B12 from the proteins. If there is a deficiency of stomach acid due to disease or medication (like proton pump inhibitors or antacids) it can cause decreased absorption and B12 deficiency. Once it is no longer protein bound, B12 binds Intrinsic Factor which is released by the Parietal Cells in the stomach. Intrinsic Factor then chaperones the B12 to the terminal ileum where it is absorbed. Pernicious Anemia is the autoimmune destruction of parietal cells which leads to less Intrinsic Factor production. Less intrinsic factor means less B12 absorption and B12 deficiency. Damage to the terminal ileum, such as in Crohn’s Disease, can also inhibit B12 absorption.

Folate and B12 work closely together handing off methyl groups to each other. It is sort of like a game of hot potato. Folate doesn’t “want” the methyl group so it passes it on to B12. B12 doesn’t “want” it either so it passes it off to methionine. In effect, B12 helps recycle methyltetrahydrofolate back into tetrohydrofolate which can be used to create DNA. This means that a deficiency of B12 can cause a deficiency of Folate as less Folate is being recycled into its “active” form. Therefore, B12 deficiency present very similarly to Folate deficiency. You get Macrocytic/Megaloblastic Anemia with Hypersegmented Neutrophils and increased Homocysteine levels.

If you mistakenly diagnose Folate Deficiency when it is really B12 Deficiency the patient will get better with Folate supplementation, but permanent neurological damage will be done overtime.

Odd chain fatty acids are broken down to eventually give Methylmalonyl CoA. B12 is a cofactor in the process that converts methylmalonyl CoA into Succinyl CoA which can then be used in the TCA cycle to generate energy. If there is not enough B12 this reaction is slowed and Methylmalonic Acid builds up. This Methylmalonic Acid build up is toxic to neurons and leads to demyelination in the posterior and lateral columns of the spinal cord. This is called Subacute Combined Degeneration and presents with peripheral numbness/tingling, spasticity, and loss of vibration and proprioception.