Folate (Vitamin B9) deficiency

Folate deficiency is a clinical condition that occurs because of low level of folate or folic acid in the body. This can lead to a variety of problems ranging from anemia in individuals from all age groups to neural tube malformation in fetuses.

Folate, also known as vitamin B9, mainly comes from eating leafy greens and citrus fruits like oranges and lemons and, nowadays, many countries fortify foods like grains and cereals with folate.

Now, folic acid present in these food items is generally in polyglutamate form, which are basically chains of an amino acid called glutamic acid.

Because of the carboxyl group present in its structure, the chain is negatively charged making it polar and soluble in water, which is a polar molecule but not soluble in lipids which are nonpolar molecules.

So the polyglutamate residues of folic acid are almost non-absorbable from the GI tract, where all the cells are surfaced with lipid cell membranes.

So, to make them absorbable, when polyglutamate residues reach a portion of the small intestine called the jejunum, special enzymes present at the jejunal mucosa cut down the polyglutamate residues into monoglutamate.

Monoglutamate is smaller, and is less negatively charged, so these monoglutamate residues of folic acids can pass through the cell membrane and enter the jejunal cells, where they are converted into tetrahydrofolic acid or in short THF by the enzyme tetrahydrofolate reductase.

These THFs then get methylated into a more stable form called methyl-THF. Once formed, the methyl-THF then leaves the jejunal cell and enters the bloodstream.

Some of it goes to the liver and get stored for a short period of 2-3 months, while most of it is used up for metabolic activity inside various cells around the body.

Folic acid is used to synthesize DNA precursors, which is essential for DNA replication and cell division.

On target cells, there’s a specialized membrane protein called Folic Acid Transporter or FAT, which moves the circulating methyl-THF inside the cell.

Once inside, methyl-THF transfers its methyl group to vitamin B12, ultimately making methylcobalamin and free THF in the process.

THF then gets an extra “methylene” group from serine, an amino acid found within the cells.

THF quickly transfers the methylene to a nucleotide called deoxyuridine monophosphate, or d-UMP for short. As a result, d-UMP becomes d-TMP or deoxythymidine monophosphate, which can then be converted to thymidine, one of the nucleotides used to build DNA.

Going back, the methylcobalamin that was formed along with THF transfers its methyl group to homocysteine and converts it into an essential amino acid called methionine, thus lowering the levels of homocysteine in the body, too much of which can be harmful.

Besides this, folic acid also plays a very important role during fetal development.

Specifically, it’s needed for the closure of the anterior neuropore of the neural tube during the 23rd day, and posterior neuropore during the 26th day of gestation. This is a crucial step in the development of the central nervous system.

So in short, the consequences of folic acid deficiency are impaired cell division, too much homocysteine in the body, and neural tube defects in fetuses.

When cell division grinds to a halt, rapidly dividing cells in the bone marrow, such as red and white blood cells, as well as platelet precursors, are affected.

Inside the bone marrow, red blood cell precursors are normally big and plump, and they undergo a series of cell divisions, which results in smaller mature RBCs.

Now with folate deficiency, at first, the bone marrow pumps out larger, but still mature RBCs called macrocytes.

These RBCs are destroyed in the spleen, which causes a decrease in the total RBC count, or anemia.

In response, the bone marrow compensates by releasing megaloblasts, which are abnormally developed RBC precursors, into the blood - and the final result is macrocytic, megaloblastic anemia.

Folate deficiency also affects white blood cell production - so the bone marrow starts releasing large, immature neutrophils.

Immature neutrophils are also hypersegmented, which means their nuclei have 6 or more lobes.

Finally, severe folate deficiency may also decrease bone marrow production of platelet precursors, which are called megakaryocytes.

So when all 3 blood cell lines are affected, this results in pancytopenia - which is when red blood cell, white blood cell and platelet count is low and this happens only in cases of severe folate deficiencies.

Other rapidly dividing cells are mucosal epithelial cells, especially those of the tongue mucosa.