Folate deficiency – causes, symptoms, diagnosis, treatment, pathology

Folate deficiency – causes, symptoms, diagnosis, treatment, pathology

Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
a personalized study plan with exclusive videos, practice questions and flashcards, and so
much more. Try it free today! 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. 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. 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 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. 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


  • Dr. Moin Khan says:

    Love you osmosis

    Please make all free videos

    Its a human thing

    Thank you brothers

  • How to Medicate says:

    Great video! Very informative on folate deficiency 👍🔥

  • tarik sahito says:

    Thanku for uploading this. I'm a premium osmosis member and please update the anemias. Website lacks that.

  • Matheus Ribeiro says:

    I love Osmosis videos in general but more often than not I feel they go into too much detail on specific and not useful information, as exemplified in this video, where all these enzymes, sub-products and precursors are explained without having any clear use in clinical practice and even in medical exams. I feel like there are many other points you guys could better cover instead of focusing on these minor details, like how to choose treatments, drug doses or important considerations.

  • KJam says:

    Where do carnivores get folate?

  • VKeisi says:

    Can't believe this video was released on the day I had a tutorial session about anemia!!! 😀


    Your videos are great…but as a high school student I don't understand…any ways to improve it?I'd like to learn more stuff from you!

  • barely blinkboy21 says:

    You said methionine is an essential amino acid. But it can be formed from homocysteine by methylation reaction. So then how can methionine be essential if it's produced by the body?

  • Laura M says:

    What role does MTHFR deficiency play?

  • Skyler Nice says:

    could you possibly do a video on depersonalization/derealization disorder?

  • We M says:

    Woow. Now everything that I had to learn by heart in medschool I can understand it now very clearly. Thank you so much Osmosis, you are helpful even in holidays 😍

  • Elizabeth Lalli says:

    Awesome & informative video, but I like Tanner’s voiceovers better.

  • Plu says:

    You forgot to mention about those people who underwent surgery for removal of the small intestine

  • First Last says:

    @8:10, Glossitis, not Glottis.

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