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In continuation with the Gastrointestinal Pathology series for undergraduates, let's learn another interesting topic in GI Pathology that is Celiac disease. Now we will look into the definition, the epidemiology, the pathogenesis, the morphology, the clinical features, diagnosis and a bit about treatment including prognosis of Celiac disease. Now what is Celiac disease?
This is also referred to as celiac sprue. It's also known as gluten sensitive enteropathy, which is basically a chronic immune mediated disorder, which is triggered by the ingestion of gluten containing foods, such as you know the wheat, the rye and the barley. And remember in genetically predisposed individuals, that's very important to note that this disease does not
know occur in every in all the individuals basically it occurs in genetically predisposed individuals. We'll talk about this a bit later. Now let's look into the origin of the name celiac disease. The celiac is from the latin word called celiacus which basically an ancient greek word called you know uh coleacus which means belly whereas sprue is an adaptation this is an english word an adaptation from the dutch sprou which was originally used to refer to persistent
Diarrhea disease in Holland, you know, probably because of celiac disease itself So that's how it was referred to as celiac sprue But then now because we know the etiology very well it is referred to as gluten sensitive enteropathy Now coming to the epidemiology The worldwide incidence of celiac disease is around 0.6 to 1 percent where the prevalence varies very widely among countries and regions
Now straight away we will move into understanding the pathogenesis of Celiac disease. So we know that gluten is the most important culprit, right? Now what is this gluten? It's basically a major storage protein which is they are deposited in starchy endosperm cells of the developing grain. And this gluten has viscoelastic properties. You know that is important when flour is mixed with water to form dough, this property plays a very major role.
Let's see how gluten looks at the molecular level. So gluten basically is made up of two proteins which is called gliadin and glutinin. See this gliadin is alcohol soluble and this is the one which gives plasticity and elasticity to the gluten whereas glutinin is water soluble and that's the one which gives strength and structure to the gluten protein. So for us.
To understand the celiac disease we need to remember that gliadin is the one which contains most of the disease producing components. So it is the gliadin component of the gluten which is the culprit in celiac disease pathogenesis. Now we know that celiac disease occurs in a genetically predisposed or a genetically susceptible host, right? But then apart from being genetically susceptible even the environmental factors

also play a major role. Now what are those environmental factors or what are the probable or proposed risk factors for development of celiac disease? They include infections including rotaviral and reoviral infection, low birth weight and antibiotic use. These are the proposed risk factor for the development of celiac disease. Now I told you genetically susceptible host. What does that mean? That means the ones who are susceptible are the individuals
who carry the genes for HLA-DQ2 and HLA-DQ8. These are basically HLA genes. There are some non-HLA genes also which basically deals with regulation of T cell differentiation, survival, migration and cytotoxicity by these T cells. They are also implicated but the most important ones are the individuals who carry these genes HLA-DQ2 and HLA-DQ8. Now let us see the pathogenesis at the cellular level. Okay.
I had mentioned that environmental factors plays a major important role, right? Now let us see those trigger factors. So whenever the cell is stressed due to any of those trigger factors which I told earlier, what happens is that these stressed cell, they express this particular antigen that is MICA which basically stands for MHC class 1 chain related protein A. This is a normal intestinal epithelium with microvilli.
and you have occasional intra epithelial lymphocytes. Okay now let's see what happens when the person consumes gluten in the diet. So gluten basically you know it is digested in the lumen of the intestines by various enzymes. Okay, one of the components which is being released after digestion is gliadin. And this gliadin you know when they interact with the intestinal epithelial cell, it stimulates the epithelial cell to produce interleukin-15.
So this interleukin 15 has a very important role. What does that do? That basically activates and results in proliferation of intraepithelial lymphocytes. So this particular lymphocyte, intraepithelial lymphocyte is now activated. Now what does that do? So once it is activated, it expresses a marker which is known as NKG2D which basically means natural killer group 2D receptor.
This marker is expressed and this marker is actually a receptor for MICA. We know that MICA is expressed in a cell which is already stressed cell. Now what happens? These MICA cells, the cells with MICA marker, they are attacked by this NKG2D expressing lymphocytes. So once this interaction happens, so what really happens is that the cell you know there
this cell is particularly damaged. So there is epithelial damage because of interaction between the telomphocytes, intra epithelial telomphocytes which are activated and then they attack the cell which carry MICA molecule, right. So the cell is damaged. If many such cells are damaged, what really happens is that the gliadin peptide now easily can enter into the lamina propria, right.
the passage of other gliadin molecules or other gliadin peptides into the lamina propria. Now in the lamina propria this gliadin is deamidated by tissue transglutaminase. So once this interaction happens the final output will be deamidated gliadin. Now this deamidated gliadin interacts with the antigen presenting cells in the lamina
And this antigen presenting cell has the receptor for the deamidated gliadin. What is that receptor? They basically HLA, DQ2 or DQ8. So once this interaction happens, so this basically stimulates CD4 positive T lymphocytes. So stimulation of CD4 positive T lymphocytes results in the production of interferon gamma, okay and many other cytokines.
which further damages the epithelial cells. So there is damage of epithelial cells by intra epithelial T lymphocytes and also by the CD4 positive T lymphocytes which are activated by the antigen presenting cells with the help of deamidated gliotin, right. So the interferon gamma damages the epithelial cells and the T cell also stimulates the other B cells to produce antibodies.
Glyadine antibodies, anti-endomycium antibodies and anti-tissue transglutaminase antibodies. So these are the antibodies produced by these activated B cells. Now you understood the concept of why there is epithelial damage and why there is increased number of intra epithelial tail lymphocytes. So that's how the epithelial cells are damaged in the intestine and that's the major mechanism of celiac disease pathogenesis.
Now we should know that interleukin-15 is a key mediator in the pathophysiology of celiac disease, right? That's because interleukin-15 as we saw it triggers activation and proliferation of intraepithelial lymphocytes, right? And that is the one which causes direct cell mediated cytotoxic effects on the small intestinal epithelium. Other than that, this interleukin-15 also renders T cells resistant to inhibition by regulatory T cells which basically means there is loss of tolerance.
Now we know the major antibodies produced by this interaction is autoantibodies to tissue, transglutaminase II and autoantibodies to deamidated gliadin peptides. These are the two major autoantibodies and there are some variants of tissue transglutaminase antibodies which can bind to transglutaminase isotypes outside of the intestine and that's why these patients also manifest skin manifestations like dermatitis, epideformis and fertility and other neurological compounds.
Now let's look into the clinical features of celiac disease. Celiac disease average age of diagnosis is around fifth decade of life and you know they present with diverse clinical manifestations and that's a challenge by itself to make a diagnosis of celiac disease. You need to have a high index of suspicion to diagnose celiac disease. So the common symptoms of celiac disease are predominantly the most common ones are gastrointestinal symptoms followed by nutritional deficiency in many patients.
and around 10% of patients they do present with skin manifestations. Now let us see what are these gastrointestinal symptoms. They include diarrhea or constipation. The constipation is more common in children. There can be abdominal pain or discomfort. There can be gas production or bloating or distension of abdomen. They can be present with delayed gastric emptying time, heartburn, steatoria and weight loss in severe cases.
In children you know there is failure to thrive and growth retardation. So that's about predominant gastrointestinal symptoms. When I talk about nutritional deficiency, because of malabsorption there can be iron deficiency with anemia, there can be deficiencies of vitamin D, vitamin B12, folic acid and even zinc and if steatoria is predominant they can manifest with vitamin A, E, R, K deficiency. And as I told you the skin manifestations can be.
There can be itchy blistering skin lesions or dermatitis herpity formus. Let's see if there are any differences between manifestations in adults and children. In case of adults, celiac disease is detected twice as frequently in women. That's because you know menstrual bleeding accentuates the effect of impaired iron absorption. Whereas in children, it affects both males and females equally and classically the symptoms begin.
after the introduction of gluten to diet that's usually around 6 to 24 months right. What are the manifestation? They present with irritability, abdominal distension, anorexia, chronic diarrhea, failure to thrive, weight loss or even muscle wasting. So that's very classical presentation in children. Now let's look into the morphology of celiac disease. Now what is the intestinal epithelial feature in celiac disease?
there can be increased number of intra epithelial lymphocytes. We know the reasons, right? So there will be disruption of normal villous architecture. Why is that so? That's because of damage of the epithelial cells by the mechanisms we studied, right? Now there can be crypt hyperplasia and villous shortening. Crypt means the bottom ones, you know, to compensate the villous loss, there can be crypt hyperplasia.
These findings are characteristic features, but they are not specific. They can be found in other diseases also. So this is a normal villi. Look at this, the villi. The villi are longer. These are the crypts. So this is a normal villi. You have occasional intraepithelial lymphocytes. And this villi are lined by colonal epithelium interspersed with goblet cells. In contrast, look at the intestinal mucosal epithelium insulac disease.
there is shortening of the villi, there is increased number of intraepithelial lymphocytes. Right? So shortening of villi and increased number of intraepithelial villi is very characteristic of celiac disease. Now, how do you diagnose celiac disease? So there are two methods of diagnosis. One is non-invasive and invasive. Okay, most often. Most often, you know, the initial, once you suspect celiac disease, the first investigation done is non-invasive methods.
What are those non-invasive methods? You demonstrate antibodies. They are IgA antibodies against tissue transglutaminase. They can be IgA antibodies against anti-endomycel antibodies. IgA antibodies are IgG antibodies against deamidated gliadin peptides. Now you can also demonstrate the absence of HLA-DQ2 and HLA-DQ8. So if you demonstrate this, it virtually rules out celiac disease. But if there is presence of HLA-DQ2 and HLA-DQ8, It's not helpful in confirming the diagnosis unless you find these antibodies. Earlier they used to do anti-glyadin antibody testing. Nowadays it is seen that it is very less specific and that's why it is no longer recommended to do anti-glyadin antibodies. Once if there is any cytological test which comes out positive, then you have to subject the patient for endoscopy and duodenal biopsy for confirmation because in the background of these antibodies, presence of antibodies.
the characteristic findings will confirm the diagnosis of celiac disease. And that's the gold standard for diagnosis of celiac disease. Now how do you treat celiac disease? Unfortunately it is the gluten free diet is the only treatment currently available. Now within 6 to 24 months of you know adherence to strict gluten free diet what happens?
There will be a resolution of symptoms, there will be reduced antibody titers, there will be restoration of normal or near normal mucosal histology and there can be reduction of the risk of long term complications. What are those long term complications? They are anemia, female infertility, osteoporosis and cancer. All these you know risk of long term complications are reduced once you adhere to a strict gluten free diet.
Now, if the symptoms persist even after adherence to strict gluten free diet, then you consider this could be a refractory sprue. That means they are not responding to gluten free diet or you can even think the possibility of cancer in a patient of celiac disease. That's what we are looking at. The sequel of celiac disease is that there is increased risk of malignancy and the most common type of malignancy is antideopathy associated.
T cell lymphoma and this malignancy is basically an aggressive lymphoma of intra epithelial T lymphocytes. We know that interleukin 15 results in stimulation of these intra epithelial T lymphocytes, right. So this is the aggressive proliferation or neoplastic transformation of this proliferation is basically enteropathy associated T cell lymphoma and second important type of malignancy is small intestinal adenocarcinoma.
So that completes the entire concept about celiac disease. We looked into the definition. We talked about the epidemiological aspect and understood in simpler terms about the pathogenesis. We looked into morphology and clinical features and the diagnosis and treatment aspect of celiac disease. Thank you for watching. If you have liked this video, hit the like button, do comment, don't forget to subscribe and do share if you find this video useful. Thank you.
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