Vitamin B12 deficiency – causes, symptoms, diagnosis, treatment, pathology

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much more. Try it free today! Vitamin B12 deficiency refers to low levels
of Vitamin B12 in the body. This can lead to a variety of problems ranging
from anemia to soreness of the tongue and neurological dysfunction. Vitamin B12, also known as cobalamin, is a
complex organometallic compound found in animal and dairy products like meat, eggs or milk. Dairy and animal products are broken down
in the stomach by pepsin, which is the active form of a gastric enzyme called pepsinogen,
to release B12. Then, a protein made by parietal cells in
the stomach, called intrinsic factor, can bind to B12, and the B12-intrinsic factor
complex passes into the intestines. When the complex reaches the terminal ileum,
the enterocytes, which are the special cells lining the intestines, recognize intrinsic
factor and absorb the whole complex. Inside the enterocytes, intrinsic factor gets
removed and a special protein called transcobalamin-II binds the free B12 and transports it into
the blood and from there, to various target tissues. Some of the transcobalamin-B12 complex gets
to the liver, where B12 can be stored for several years. B12 is used to synthesize DNA precursors,
which is essential for cell division. First, vitamin B12 accepts a methyl group
from methyl tetrahydrofolate or methyl-THF, making methylcobalamin and free tetrahydrofolate,
or 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. Alternatively, B12 can be used by the mitochondria
in another active form called “adenosylcobalamin” – which is basically B12 with an adenosyl
group clinging to it! Adenosylcobalamin acts as a coenzyme for methylmalonyl
coenzyme A mutase, an enzyme which converts methylmalonyl co-A into succinyl co-A. This
helps reduce the levels of methylmalonic acid, which can also be harmful if it builds up. So in short, the consequences of B12 deficiency
are that cell division is impaired, and there’s too much homocysteine and methylmalonic acid
in the body. When cell division grinds to a halt, rapidly
dividing cells in the bone marrow are affected, like red and white blood cells, as well as
platelet precursors. 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 B12 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 abnormally developed RBC precursors, called megaloblasts, into the blood, and the
final result is macrocytic, megaloblastic anemia. B12 deficiency also affects white blood cell
production – so the bone marrow starts releasing large, immature neutrophils, with hypersegmented
nuclei – meaning their nucleus has more than 5 lobes. Finally, severe B12 deficiency may also decrease
the production of megakaryocytes, which are the platelet precursors in the bone marrow. 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 folate deficiency also decreases white
blood cell, red blood cell, and megakaryocytes production in the bone marrow, also resulting
in pancytopenia. 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, not literally that fast, but it is pretty
quick. In B12 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. They also build up in the blood, where they
bind 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 build
up 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 there’s too much methylmalonic
acid in the body, it builds up in the neurons – specifically, in the myelin sheath, which
degenerates. Myelin helps transmit electrical impulses
from one neuron to another at very high speed – so with B12 deficiency, communication between
neurons gets significantly slower, which leads to impairment of neurological and muscle function. Kinda like the difference between optic fiber
and the old dial-up internet connections. Ok, now, B12 deficiency can result either
because of impaired absorption or decreased dietary intake. Impaired absorption can result from a number
of causes. For example, in pernicious anemia, there’s
increased production of overzealous IgA antibodies against intrinsic factor or the parietal cells. Either way, this interferes with intrinsic
factor’s ability to bind to B12. In Crohn’s disease, the enterocytes in the
terminal ileum are often damaged, so B12 can’t bind to transcobalamin to get to the target
tissues. In people that get a gastric bypass, the ingested
food passes through the stomach quickly, so even if intrinsic factor is produced, it can’t
get to the food to bind B12. Besides these, infestation in the terminal
ileum with Diphyllobothrium latum, also known as fish tapeworm, or bacterial overgrowth
in the blind loop of bowel can also reduce absorption, leading to vitamin B12 deficiency. Decreased dietary intake is seen in individuals
who avoid all animal products – like long time strict vegans who don’t take B12 supplements. Now, B12 deficiency most commonly causes signs
and symptoms of anemia like pallor, shortness of breath and easy fatigability; 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, in very severe cases, B12 deficiency
may lead to impairment of neurological function, where individuals present with loss of memory
function, decreased reflexes and psychosis. Diagnosis of vitamin B12 deficiency relies
on a peripheral blood smear, which shows large red blood cells and hypersegmented neutrophils. On a blood sample, a Mean Corpuscular Volume
or MCV, larger than 100 fL suggests macrocytosis. A bone marrow study can also be done to look
for the megaloblastic changes in RBC precursors at various stages of differentiation. Homocysteine and methylmalonic acid levels
are also elevated. After confirming that there is a B12 deficiency,
the cause should be found. First, low dietary intake should be ruled
out. Then, to pinpoint the cause of decreased absorption
– one can look for anti-intrinsic factor antibodies for pernicious anemia, or carry out endoscopic
or imaging studies in patients that might have Crohn’s disease. When the cause of B12 deficiency is dietary,
it’s treated with oral B12 supplements. When the problem is absorption related, it
could be treated with either really high oral B12 doses to allow for passive diffusion in
the gut, or with intramuscular B12 injections for a couple of months, which can be followed
with oral supplements if needed. Additionally, treatment of the underlying
cause, when possible, should also be started. Alright, as a quick recap…Vitamin B12 deficiency
is a clinical condition caused by low levels of Vitamin B12 in the body, which impairs
cell division and causes excess levels of homocysteine and methylmalonic acid in the
body. This can lead to macrocytic megaloblastic
anemia causing pallor, shortness of breath and fatigability; glossitis or inflammation
of tongue leading to swelling and soreness, difficulty in talking and swallowing; and
myelin damage resulting in changes in reflexes, poor muscle function, memory problems, and
psychosis in some extreme cases. Diagnosis of B12 deficiency can be made by
doing a peripheral blood smear, measuring the MCV and serum levels of vitamin B12, as
well as serum homocysteine, and methylmalonic acid levels. B12 deficiency is treated with, well, B12
– either as oral supplements or intramuscular injection.