Vitamin B12 deficiency

Definitions & Key takeaways

Vitamin B12 deficiency is a clinical condition caused by insufficient levels of Vitamin B12 in the body, which hinders cell division and causes an excess of homocysteine and methylmalonic acid. This can result in macrocytic megaloblastic anemia, characterized by pallor, dyspnea, and fatigue; glossitis or inflammation of the tongue, resulting in swelling and tenderness, dysphonia, and dysphagia; and myelin damage, which may lead to changes in reflexes, decreased muscle function, memory impairment, and, in rare cases, psychosis. Diagnosis of B12 deficiency can be confirmed by conducting a peripheral blood smear, measuring serum levels of vitamin B12, as well as serum homocysteine and methylmalonic acid levels. B12 deficiency is effectively treated with oral supplements or intramuscular injections of vitamin B12.

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Introduction0:00–0:16

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.

Physiology0:16–2:45

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.

Pathophysiology2:45–6:06

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.

Causes6:06–7:18

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.

Symptoms7:18–7:52

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.

Diagnosis7:52–8:51

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.

Treatment8:51–9:18

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.

Recap9:18–10:06

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.