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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, theres 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 extramethylenegroup from serine, an amino acid found within the


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, its 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


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.

Have you ever noticed how fast your tongue heals if you accidentally bite it?

Thats because old epithelial cells are replaced with new ones in the blink of an


Okay, its not literally that fast , but it is pretty quick.

In folate deficiency, old epithelial cells arent replaced, and this slows down the

healing of normal wear and tear of the tongue, which ultimately leads to inflammation of

the tongue, known as glossitis.

Next, when homocysteine builds up in the body, some of it is excreted in the urine leading

to homocystinuria.

It also builds up in the blood, where it binds to the endothelial cells lining blood vessels,

causing them to secrete molecules called proinflammatory cytokines.

These attract immune cells like leukocytes to the area and cause inflammation, which

leads to atherosclerosis, or plaque buildup inside the arteries.

This narrows the arteries and could lead to ischemia of the tissue supplied by them.

Homocysteine also binds to platelets and makes them stick together to make blood clots.

All of this increases the risk of ischemic heart disease and stroke.

Lastly, when pregnant women suffer from folate deficiency around the time of conception,

embryos may not properly develop the neural tube due to impairment in the closure of anterior

and posterior neuropore of the neural tube, which may lead to neural tube defects.

So, when the anterior neuropore doesnt close properly, the baby may be born with

anencephaly or absence of a major portion of the brain and the skull.

Similarly, if the posterior neuropore doesnt close well, the baby may be born with spina

bifida or incomplete closure of the vertebrae and membranes of the spinal cord.

Ok, now, folate deficiency can result because of increased demand, decreased dietary intake

or impaired absorption.

Normally, we have up to 2 to 3 months supply of folate in the body, but this can get used

up even quicker during pregnancy due to the increased need for it.

So generally, people who get folate deficiency are either pregnant, or have had an extremely

restricted diet for longer than six weeks.

Besides this, excessive alcohol consumption and medications like phenytoin, trimethoprim,

sulfasalazine and methotrexate often interfere with folic acid absorption from the jejunum.

Folate deficiency most commonly causes signs and symptoms of anemia like shortness of breath,

pallor, and easy fatigability; as well as soreness of the tongue due to glossitis.

In some cases, they may also present with signs and symptoms of ischemic heart disease,

like chest pain, or signs of stroke, like slurred speech and paralysis.

Lastly, long-standing cases of severe folate deficiency may also present with features

of pancytopenia like anemia due to low RBC count, recurrent infections due to low WBC

count and bleeding tendencies due to low platelet count.

Diagnosis of folate deficiency relies on a peripheral blood smear, which shows large

red blood cells.

On a blood sample, a Mean Corpuscular Volume or MCV, larger than 100 fL suggests macrocytosis.

Homocysteine level is also elevated.

A bone marrow study can also be done to look for the megaloblastic changes in RBC precursors

at various stages of differentiation.

After confirming that there is folate deficiency, the cause should be found.

First, low dietary intake should be ruled out, and a pregnancy test should be done.

Then, the history can help identify other causes, like medications or excessive alcohol


When the cause of folate deficiency is dietary, its treated with oral folate supplements.

When the problem is absorption related, it has to be managed by stopping the offending

medications or limiting alcohol consumption.

Lastly, in pregnant people, folate deficiency can be avoided by providing folate supplements

or fortifying foods like grains and cereals with folate.

All right, as a quick recap, folate deficiency is a clinical condition caused by low levels

of folate in the body, which impairs cell division and causes excess levels of homocysteine

in the body.

This can lead to neural tube defects in fetuses, macrocytic megaloblastic anemia causing pallor,

fatigability and shortness of breath; glossitis or inflammation of tongue leading to swelling

and soreness, difficulty in talking and swallowing.

Diagnosis of folate deficiency can be made by doing a peripheral blood smear, measuring

the MCV and serum levels of vitamin folate, as well as serum homocysteine levels.

Folate deficiency is treated with folate supplements, folate-fortified food items, by stopping the

offending medications or limiting alcohol consumption.

The Description of Folate deficiency - causes, symptoms, diagnosis, treatment, pathology