Celiac disease – causes, symptoms, diagnosis, treatment & pathology

It’s becoming more and more common to see
things like “gluten-free pizza” or “gluten-free buns” at restaurants, grocery stores, or
other food-based businesses. This is partly because there’s this increasing recognition,
awareness and diagnosis of a disease called celiac disease, sometimes called celiac sprue,
and as many as 1 in 100 north americans are diagnosed with it. Celiac disease is currently understood as
an immune system-mediated disorder where the gluten in food triggers the body’s immune
cells to attack the cells in the small intestine. Gluten’s found in all sorts of wheats and
grains, including rye and barley. If we take a look at wheat, you’ve got your individual
wheat kernels, and then inside each kernel’s there’s the endosperm, which has a bunch
of nutrients for the seed’s embryo, mostly protein and starch, and some vitamins. The
type of protein here is gluten, the main culprit in Celiac disease. Well, really the main culprit
behind celiac disease is a 33 amino acid peptide component of gluten called gliadin. Okay,
so the gliadin in gluten is what triggers immune attack in Celiac disease, hence the
need for gluten-free pizza or buns in hamburgers, right? Well, that’s not the whole story…since
we’ve known about Celiac disease for quite some time, like 70 years. So why the recent
push? Well, within the last few years there’ve been proposals of non-celiac gluten-related
disorders, like gluten sensitivity, where gluten is thought to cause GI symptoms that
seemingly improve when gluten’s taken out of the equation. Unfortunately, as of this
moment in February 2016, there’s very little solid scientific evidence to back a removal
of gluten from the diet unless you have celiac disease, although some people do seem to have
improved GI symptoms on a gluten-free diet, whether that’s from removing gluten specifically,
or a more broadly, an adherence to a diet that’s typically much lower in processed
foods and carbohydrates, remains to be seen! Alright, back to celiac disease, so, if somebody
with celiac disease eats a wheat-based pizza, it’s broken down in the stomach into gliadin…and
a whole lot of other stuff, gliadin’s a tough little bugger though and resists being
broken down by all sorts of enzymes. When gliadin gets to the small intestine, it’s
bound to secretory IgA in the mucosal membrane, which is an antibody that helps protect gut
epithelial cells called enterocytes from toxins and pathogens. Usually, things bound to secretory
IgA are marked for immune cell destruction, but in Celiac diseasve, this gliadin-IgA complex,
for some reason, binds to a transferrin receptor, TfR, which is usually used to help absorb
iron and seems to be over-expressed in patients with Celiac disease. Once bound to the receptor,
it’s trancytosed across the cell from the apical to the basolateral membrane, or across
the enterocyte and into the lamina propria which is a thin layer that lines the gut wall.
Once there, an enzyme called tissue transglutaminase, or tTG, cuts off of an amide group from the
protein. Deamidated gliadin’s then eaten up by macrophages and served up on its MHC
class II molecules. Remember, macrophages are in the gut and are always doing a bit
of “gut sampling” where they grab proteins (which a lot of times are from foods that
we’ve eaten) and show them to the immune cells. MHC stands for Major Histocompatibility
Complex and is that name of the “serving platter” for the stuff that is served up.
It’s a normal way to make sure that there are no pathogenic bacteria lurking in the
gut. Now there are a ton of different types of
MHC class II “serving platters” and these serving platters are encoded by genes called
human leukocyte antigen genes, or HLA genes. These genes determine what things the MHC
class II molecules “serve up”, so, for example, HLA-DR encodes
for an MHC that “serves up” something different than the one HLA-DQ encodes for.
. Researchers have noticed that patients with celiac disease typically have specific deamidated
gliadin “serving platters” such as one called HLA-DQ2 or HLA-DQ8, which is an interesting
clue that helps us better understand celiac disease. It’s at this point—where the HLA protein
“serving platter” serves up gliadin—that the immune system kicks in. The macrophage
throws it up top and is like “hey, uh, guys? What do you think about this molecule…?”
and T helper cells, also known as CD4+ T-cells, from the immune system that recognize the
gliadin zoom over and are like “Yep, I’ll take it from here”, and they release inflammatory
cytokines, molecules that initiate inflammation, like interferon gamma and tumor necrosis factor,
which can directly damage and destroy epithelial cells in the villi of the small intestine.
Not only that though, the helper T cell stimulates B cells to start pumpin’ out IgA antibodies
against the gliadin, the transglutaminase enzyme, and endomysial antibodies, or EMAs,
which are actually another type of antibody for transglutaminase, but for the transglutaminase
found in the endomysium, a layer of connective tissue around muscle fibers. It’s not totally
understood why these are produced since they don’t seem to cause any muscle related damage
or symptoms; it’s possible they’re produced simply because of their structural similarity
to the transglutaminase in the lamina propria. They are, however, helpful in making a diagnosis.
Finally, the helper T cells also recruit killer CD8+ T cells, which is when things get nasty.
Killer T cells are drawn to and destroy cells undergoing inflammation. So, in short, as
patients eat gluten, the immune system is stimulated and epithelial cells are destroyed.
It’s possible that the destruction of these cells lets more gliadin across the epithelium,
since they’re not bunched together as tightly as they were before. Tests for the antibodies in the blood can
be used clinically to help screen for celiac disease, IgA blood tests for both tTG and
endomysial tTG can be effective ways to determine whether someone has Celiac disease, especially
in more severe cases, although for more common, mild forms of Celiac, these tests are less
effective. Tests for IgA or even IgG antibodies against gliadin may also be used. For reasons
that aren’t well understood, a small amount of the patients are IgA deficient, meaning
they aren’t able to produce any IgA antibodies in general, so in this case they’d need
to have an IgG screening test done. Now this whole fiasco mainly happens in the
duodenum, probably because it’s the first part of the small intestine and so the first
to be exposed to gluten, the jejunum and ileum are also involved, but the duodenum is where
most of the damage goes down. So a biopsy of the duodenum shows pretty clearly the extent
of the damage. Healthy duodenum should look like this, where you have these really tall
villi and these crypts that don’t go down too far. With celiac disease, these villi
can be destroyed and flattened out, called villous atrophy, and the crypts can get longer;
these changes are called crypt hyperplasia, possibly from infiltration of immune cells
or from the remodeling process that begins to take place during chronic inflammation.
You’ll also be able to see this infiltration of immune cells, or lymphocytes, in the epithelium.
An endoscopic biopsy of this tissue can be an effective, yet more invasive way to diagnose
celiac disease. Children with celiac disease often present
with symptoms like abdominal distension or bloating, as well as failure to thrive and
diarrhea. Adults typically have chronic diarrhea and bloating as well, but the symptoms vary
wildly. Also, patients can frequently have dermatitis herpetiformis as a complication,
which actually has nothing to do with the herpes virus. It’s actually a bumpy skin
rash that pops up from circulating IgA antibodies in the blood, where they mistakenly bind to
the transglutaminase in the dermal papillae of the epidermis. Once they’ve bound, neutrophils
swing by and start up an inflammatory reaction that’s noticed on the skin as this rash. Now, the main bad guy in this whole story
that provokes the immune system and causes this whole mess, is gluten. So symptoms and
issues typically resolve when patients adapt a gluten-free diet. For some patients that
start to adhere to a gluten-free diet, even for many years, there’s still an increased
risk of refractory disease, like small bowel cancer and T-cell lymphoma, presumably due
to inflammation and immune system activation over time.