Folate (Vitamin B9) deficiency

Definitions & Key takeaways

Folate (vitamin B9) is a water-soluble vitamin that is mainly found in leafy green vegetables and fruits. It is important for the development of new cells, and it helps to form red blood cells. A folate deficiency can lead to anemia, and it can also increase the risk of neural tube defects in newborn babies. Symptoms of a folate deficiency can include fatigue, shortness of breath, and a pale complexion.

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Introduction0:00–0:33

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.

Physiology0:33–3:37

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.

Pathology3:37–7:05

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. Have you ever noticed how fast your tongue heals if you accidentally bite it?
That’s because old epithelial cells are replaced with new ones in the blink of an eye! Okay, it’s not literally that fast , but it is pretty quick.
In folate deficiency, old epithelial cells aren’t 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 doesn’t 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 doesn’t close well, the baby may be born with spina bifida or incomplete closure of the vertebrae and membranes of the spinal cord.

Causes7:05–7:42

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.

Symptoms7:42–8:21

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.

Diagnosis8:21–9:30

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 consumption. When the cause of folate deficiency is dietary, it’s 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.

Review9:30–10:21

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.