You can see gluten-free food almost everywhere.
What’s the big deal?
Well, around 1% of the world population can’t eat gluten or else they will experience stomach
pains, diarrhea, or even malnutrition.
This is because these people suffer from a condition called celiac disease.
Watch this episode of Medicurio to learn the history, symptoms, mechanism, and treatment
of celiac disease.
Celiac disease symptoms were first recorded 2000 years ago by the Greek physician Aretaeus,
who observed his patients suffering from diarrhea and malnutrition.
He named the disease “koiliakos” (κοιλιακός), meaning “abdominal” in Greek, which later
became “coeliac disease” when his work was translated.
The cause of celiac disease was much later discovered by Dr. Willem Karel Dicke during
the Dutch famine of World War 2.
During this time, delivery of bread to hospitals was halted, but Dr. Dicke observed that his
patients with celiac disease paradoxically improved.
When supplies began being delivered again after the war, his patients deteriorated.
Dr. Dicke realized that wheat intake, specifically gluten intake,
was the main cause of celiac disease.
But what’s gluten?
Gluten is a group of proteins found in wheat, barley, and rye. For example, in wheat,
the gluten proteins are gliadin and glutenin.
Derived from the Latin word for “glue”, gluten is responsible for making dough elastic
and sometimes used as a thickener.
So, it’s not surprising that it is found in most baked goods, pasta, cereals, beer,
and even some processed foods lik French fries and canned soups.
What happens when someone with celiac disease eats any of these products?
Let’s discuss the symptoms.
The small intestine is where our body absorbs the nutrients and water from the food we eat.
If we take a section of the small intestine and zoom into the inner surface, we can see
that it is covered with finger-like protrusions called villi.
This increases the surface area available for nutrient and water absorption, compared
to if the inner surface were flat.
Let’s zoom in even further.
Nutrients and water can cross the intestinal epithelial cells, enter a layer of intestinal
tissue called the lamina propria, and eventually reach the bloodstream.
You can see that even the epithelial cells have small protrusions, called microvilli,
that further increase surface area for absorption, highlighting how important surface area is
in the small intestine.
There are also immune cells called intraepithelial lymphocytes which hang out between the epithelial
cells and kill any infected or unhealthy cells.
Zooming back out, we can see that between these villi are indentations called crypts,
which play a role in replenishing dead epithelial cells.
In people with celiac disease, gluten initiates an autoimmune reaction
that damages the intestinal wall.
Intraepithelial lymphocyte numbers skyrocket and kill the epithelial cells, resulting in
shorter and flatter villi, while crypts deepen as the intestine tries to replenish the dead
epithelial cells.
Now there is reduced surface area, meaning less nutrient absorption.
Less water and fat absorption in the small intestine leads to diarrhea and steatorrhea,
while less nutrient absorption may result in weight loss, fatigue, anemia, osteoporosis,
or even increased bleeding risk.
Furthermore, bacteria that live in the small intestine can use up the unabsorbed nutrients,
releasing gas that causes bloating.
Celiac disease can show up as any combination of these symptoms, making it very difficult for
doctors to diagnose, or even consider, celiac disease to be the cause of their patient’s discomfort.
This is why scientists estimate that around 80% of people with celiac disease have not
been correctly diagnosed.
This is a serious problem because if left untreated, celiac disease can lead to neurological
damage, infertility, or even cancer.
So let’s take a closer look to see how gluten triggers this intestinal damage.
While most proteins are broken down into individual amino acids or small peptides in the small
intestine, our digestive enzymes simply cannot break down gluten proteins very efficiently because
gluten proteins contain high amounts of two amino acids: proline and glutamine.
This results in large gluten peptides that cross the epithelial cells and enter the lamina
propria in a few different ways.
Overexpression of the zonulin gene creates
wider gaps between cells for gluten peptides to enter.
Gluten peptides can also be transported across cells by binding to receptors.
And finally, there seems to be evidence that certain gluten peptides can directly damage epithelial
cells, creating openings for more gluten peptides to flow through.
Once inside the lamina propria, these peptides are then modified by an enzyme called tissue
transglutaminase, which is normally found within cells but released and active during
tissue damage.
This enzyme changes the glutamine residues to glutamate, resulting in a more negatively
charged peptide fragment.
Remember this step – it will be important later.
Now, the immune system gets involved.
The intestinal tissue is constantly patrolled by dendritic cells, which play a huge role
in alerting the immune system if they find anything harmful.
The way they do this is by presenting peptides they have found in the environment on their
surface by using special display proteins called MHC class II proteins.
For example, during a bacterial infection, many bacteria are in the environment, and
so the peptides displayed on the surface of dendritic cells
would likely be from a bacterial protein.
Helper T cells, the main regulators of the adaptive immune system, will then “check”
if their unique T cell receptor can bind to the peptide.
If it can, that helper T cell is activated, proliferates, and starts the immune response.
T cell receptors are designed so that they won’t bind to any peptides normally found
in our body, so helper T cells are only activated when they find something that doesn’t belong
in our body.
In the case of gluten, modified gluten peptides are found and displayed by dendritic cells
on their MHC class II proteins.
Since gluten peptides aren’t found in our body, the appropriate helper T cell is activated.
These helper T cells have three functions.
First, they release inflammatory molecules to cause stress to the epithelial cells.
Helper T cells also release molecules that cause activation and proliferation
of intraepithelial lymphocytes,
which recognize and kill these stressed epithelial cells, causing more gluten peptides flow in
to exacerbate the situation.
Finally, helper T cells activate B cells which make antibodies against these gluten peptides,
as well as against tissue transglutaminase.
Though the extent of damage caused by these autoantibodies is not well understood, they
play a key role in diagnosis as you will see later.
To summarize: eating gluten-containing food starts a positive feedback loop where damage
makes it easier for more gluten to enter, worsening the situation and resulting in the
symptoms mentioned earlier.
This brings up an interesting question: Why do some people have an immune response to
gluten, while most people do not?
This can be explained by the variations in MHC class II molecules.
There are three main types of MHC class II molecules: HLA-DP, DQ, and DR.
These three types also have many different isoforms, each of which have a different binding
pocket, allowing it to bind to different peptides.
Each person has 2 isoforms of each type, inherited from each parent, making each person’s combination
of MHC class II molecules, as well as the range of peptides their dendritic cells can
present, slightly different from another person.
The only isoforms that can bind to gluten peptides are HLA-DQ2 and HLA-DQ8, which bind
extremely well to negatively charged peptides such as the gluten peptides modified by tissue
transglutaminase as mentioned earlier.
Without HLA-DQ2 or 8, dendritic cells cannot present gluten peptides to activate T cells.
So it makes sense that virtually all people with celiac disease
have either HLA-DQ2 or 8.
The prevalence of these isoforms varies between racial groups. For example, HLA-DQ2 is
found in less than 5% of Japanese people but in around 25% of European Caucasians.
This explains why the rates of celiac disease differ so widely across the world.
Interestingly, not all people with HLA-DQ2 or 8 develop this disease.
For example, only 4% of Caucasians with HLA-DQ2 develop celiac disease.
Why is this the case?
While the specifics are not well understood, scientists agree that additional genetic and
environmental factors play a huge role.
Mutations in immunoregulatory genes may make immune cells more reactive.
Perhaps other mutations make the intestinal epithelium permeable, allowing easy entry
by gluten peptides.
As for environmental factors, scientists hypothesize that having an intestinal infection while
eating gluten may play a role in developing celiac disease.
Normally, T cells will not react to proteins found in food because the dendritic cell will
release cytokines like IL-10 that suppress the T cell.
However, if an infection is going on, dendritic cells want to activate T cells to fight the
infection, so they no longer release IL-10.
If a person eats gluten during an infection, these dendritic cells will present both viral
and gluten peptides.
T cells that recognize the presented gluten peptide are no longer suppressed by IL-10
and therefore will react to it, leading to celiac disease.
Essentially, the immune system thinks that the gluten peptide is from the virus and attacks
it accordingly.
So, to develop celiac disease, not only do you need to have HLA-DQ2 or 8 so your dendritic
cells can present gluten peptides to helper T cells, but you also need certain environmental
and genetic factors that cause your immune system to react to these gluten peptides.
Now that we understand the cause and effects of celiac disease, let’s discuss who gets
this disease, how to detect it, and how to treat it.
As mentioned earlier, having HLA-DQ2 or 8 puts you at a much higher risk of developing
celiac disease, and explains why celiac disease rates are different for different racial groups.
Celiac disease affects all ages, but is more commonly diagnosed in older people.
It is also more common if you are suffering from an autoimmune disorder such as type 1
diabetes or multiple sclerosis.
Finally, since MHC class II molecules are inherited, if your parents, siblings, or children
have celiac disease, you are at a 10 times higher risk of also having celiac disease.
Please talk to your physician to get tested if you are experiencing celiac disease symptoms,
or if your family members have celiac disease.
But what are these tests?
Since antibodies against tissue transglutaminase are produced and released into the blood in
celiac disease, testing for the presence of these antibodies is often the first and easiest
way to check for this disease, but is not 100% accurate.
To confirm a diagnosis, doctors will have to perform an upper gastrointestinal endoscopy,
in which they insert a thin, flexible camera called an endoscope down your throat and into
your intestines to check for intestinal damage.
At the same time, doctors will get a sample, or biopsy, of intestinal tissue that is analyzed
under the microscope.
If intestinal damage is seen, such as villous blunting, crypt hyperplasia, and increased
intraepithelial lymphocytes, then a diagnosis for celiac disease is confirmed.
Keep in mind though that this test requires you to eat gluten-containing foods for 6-8
weeks for the antibodies to build up and damage to be detected. This should only be done
under the supervision of a dietician or trained physician.
Finally, you can get genetic testing to see if you have HLA-DQ2 or 8.
If you don’t have these isoforms, great! Because it’s virtually impossible for you
to develop celiac disease.
If you do have them though, it doesn’t necessarily mean you will develop celiac disease,
but it does put you at an increased risk and more tests should be
performed throughout your life.
This is mostly done by the relatives of people with celiac disease to rule out the possibility
of developing celiac disease themselves.
Since eating gluten is the reason why the intestines get damaged, the only effective
treatment available is going on a gluten-free diet.
This stops the immune system from attacking the intestines, allowing the intestines to
heal and symptoms to dissipate.
Gluten free diets are very difficult to adhere to due to the prevalence of gluten in food,
making the lives of those who suffer from celiac disease difficult and often frustrating,
as they are no longer able to eat things they enjoyed in the past.
This is getting better because of all the gluten-free alternatives,
So it's a step in the right direction.
New therapies are also currently being developed that target certain areas of the celiac disease
cycle, so the future seems bright for people with celiac disease.
Still curious about celiac disease?
Wondering how celiac disease is different from wheat allergies, or why many celiac patients
also develop rashes?
And what is refractory celiac disease?
You can learn all that and more in the video description below.
Thanks for watching, and see you next time on Medicurio.