Celiac - clinical Flashcards
Celiac disease - What’s celiac’s disease +prevalence
Is an autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to inflammation + damage in intestine. = food intolerance
Effects 1/100 people
Gluten is found in grains
Dutch pediatrician discovered it in WW2, and found that gluten causes it. Very common disease. Large patients of patients aren’t diagnosed.
There’s around 170k patients in Netherlands, but only 25k is known.
Females effected more 3:1 compared to males, like many autoimmune diseases.
Finland = higher seen. More than %1, geographic differences seen, probably due to genetic background.
Where the name Celiac comes from?
Where the name comes? Comes from a patient lived 2000 years ago, and in one of his books he gave very detailed description of this disease.
If stomach is irretentive of food and it passes undigested = we call them coeliacs.
Coeliac = means abdomen/belly in Greek.
What happens to celiac disease patients? - steps of digestion
Main symptom of celiac disease is malabsorption. = Food isn’t properly digested, and lost inside the stool.
Mechanical + enzymatic breakdown, (luminal factors)
absorption (mucosal factors)
and transportation of food is required.
If any of those go wrong, you can get malabsorption.
Food enters from mouth, chewing + saliva amylase breaks down the carbohydrate, goes to stomach = it contracts and mechanically breaks down the food, also adds acid + pepsin to break down to peptides, food goes to intestine = again enzymes coming from pancreas break down the food more. = lipids, monosaccharides, and amino acids that can be absorbed by body.
Major part of the food is absorbed in upper part of GI in duodenum + jejunum, remaining is absorbed in ileum. Vitamin B12 is absorbed in lower parts of intestine, and its where Crohn’s disease occur, so people with Crohn’s disease might have Vitamin B12 deficiency.
Mechanical factors are necessary for breakdown of food like stomach movements. + Enzymes = pepsin in stomach. And mainly enzymes come from the pancreas.
Luminal factor diseases
Chronic pancreatitis: alcohol Zollinger Ellison Liver diseases Bacterial overgrowth If a gallstone pushes the pancreas, you can also get inflammation, leading to less enzyme production.
Mucosal factor diseases
Loss of mucosal surface (shorter bowel)
Inflammation, iscemia, cancer, mucosal diseases like Crohn’s + celiac
If you lose some of your mucosa, you might simply not have enough surface to absorb all nutrients. It can also occur if GI is sick due to inflammation
Clinical signs of malabsorption
+ Clinical signs of celiac
Loss of calories/weight loss
Diarrhea: Many of the nutrients that are normally absorbed by small intestine go to large intestine, and there they attract a lot of water from the body and that causes diarrhea.
Flatulence
Abdominal pain: Since carbohydrates aren’t absorbed and enter to colon, there’s a lot of bacteria there, and these carbohydrates get fermented – and it causes a lot of gas, leading to swollen cramped abdomen.
Deficiencies due to not absorption of electrolytes, Fe, vit B12, folic acid, Ca etc.
Anemia: Since a lot of vitamins / electrolytes can be absorbed, and some of them are strictly needed in hematopoiesis
not taking enough Vitamin B12, folic acid and Iron. Without diarrhea and very clear symptoms, Anemia can point out Celiac.
Calcium + Vitamin D = crucial for bone turnover, so if you don’t have them you can’t get good bone density.
Additionally: Celiac patients might have:
No good growth in kids
Fatigue: very common complaint in autoimmune diseases - many people keeps repeating that they are always tired, might be undiagnosed Celiac.
Might be mild/no symptoms. %80 of people are undiagnosed.
Constipation
Infertility = not known why
Also you can develop extremely rare autoimmune diseases outside the intestine, eg. dermatitis herpetiformis
very rare neurological problems can also be seen.
Diagnosing malabsorption: Stool analysis
3 days of what to eat, calculate calories, and collect stool = analyse.
Normal person produces 150-200 gram feces in a day, severe diarrhea might get it up to 4000 grams. 4 kg of shit per day. Shit is %70 water, %30 other things normally, in diarrhea water increases.
Independent on what we eat, our absorption is actually efficient, so we only lose a few part of the nutrients during absorption. If a patient’s stool float on the water = too much lipid on shit, malabsorption. Amount of protein by Nitrogen can be calculated, also calorie loss can be counted, normally we lose 150-200. Severe malabsorption can lead to a lot of loss.
Celiac disease pathogenesis + what’s gluten
Grain has bran + endosperm + germ. Found inside the soil, sees no sunlight. It has a lot of energy inside, the endosperm part, and we eat it inside the bread. Contains %65 of carbohydrate, %15 contains protein and this protein is largely gluten.
Gluten is composed of glutenins and gliadins, and they can pass the epithelial layer.
Wheat, rye and barley are genetically very related = people that have Celiac disease can’t tolerate the gluten inside neither of them. Usually they tolerate oat, rice, maize though, since they are more different from the gluten.
We eat many proteins; why Celiac disease patients can’t specifically tolerate gluten directly?
Related to their composition, gluten proteins have high Glutamine (Q) and Proline (P) levels.
They are resistant to pepsin digestion in stomach.
Gluten immunization steps:
Why gluten causes immune activation?
1) Food uptake, gluten slightly degraded in stomach but still very large
2) They go to duodenum, in mucosa there’s a lot of inflammatory cells, eg. APCs.
3) Gluten is taken by APCs. If you have HLA-DQ 2 or 8 (%40 of population) = gluten can bind to MHC and presented to a naïve T cell.
4) This causes a bit of mucosal damage, but the villi are still there on tissue.
5) But then, due to inflammation, transglutaminase is secreted, and they bind to gluten and process it. They deaminate the gluten to a different peptide.
6) Because of the deamination, they change conformation, that binds even stronger to the HLA-DQ 2-8. This leads to much stronger inflammation, and mucosa is much more damaged, and villi is gone, and immune cells gather around.
7) Autoimmune part? Transglutaminase + gluten complex = recognized by B cells! = auto Ab production. = transglutaminase Abs. These Abs can be measured.
Cure of celiac’s - safest treatment + problems
Stop eating gluten? It won’t bind to HLADQ, won’t activate T cells, and drive transglutaminase release from inflamed tissue, and no auto Abs will be generated. = Problem solved!
symptoms disappear, mucosa heals, villi restored. Very safe, cheap, effective, simple.
Problem: Gluten is in almost every food. = They need to check what they eat every day. Also you can’t eat less gluten, it has to be absolutely gluten-free, otherwise it doesn’t work, independent on the strength of the response they give against gluten. Can be a burden for patients. Also the more patients continue with gluten free, the more intolerant they become, they can tolerate less and less.
Like in allergen immunotherapy, give less and less every day and get immune to it? clinical trials are done for it = didn’t work.
Antibodies in celiac disease - Serology diagnostics + children diagnosis
Transglutaminase Ab:
If you have Celiacs, you develop transglutaminase Ab with gluten, which can be identified with ELISA or by an indirect immunofluorescence technique called Endomysium Abs.
Children diagnosis:
Important for diagnostics, indeed in kids, only transglutaminase Abs are checked, and if they are very high the diagnosis is done.
1) Symptoms observed
2) X10 Transglutaminase Abs
3) Endomysium Abs positive = children is diagnosed with Celiac. No endoscopy on kids.
This finding needs to be proven in an another blood sample taken = since it’s a huge burden for rest of patient’s life and they will eat gluten free forever, important to recheck.
If it’s lower than x10, need endoscopy.
Even without complaints, if you have 10X, you can be diagnosed.
The Ab levels can be checked to make sure patients are following a good diet as well.
Why only HLA DQ 2-8 can develop Celiac?
They perfectly fit in the groove + bind very strongly of those HLA due to their amino acid sequence.
De-aminated version binds even better.
Paradox of celiac disease development - HLA
%40 of population has HLA DQ 2-8
Only %1 develops Celiac!
%1 develops disease= so there must be many different factors crucial to develop the disease.
And we don’t know what actually causes it, why only few of the susceptible people gets sick isn’t know.
Hypothesis: Your mucosal barrier gets more permeable, for ex. due to an infection, and it temporarily allows higher load of these peptides in mucosa = starts the disease. But nothing proven.
Celiac diagnosis time
Large proportion of Celiac Disease starts in early childhood, above %50 though the disease is diagnosed in 40-50 years. Some of those are undiagnosed patients, but it’s also known that you can develop the stage from start in later ages! Patients at age 25-30, completely normal endoscopy, then 40-50 = Celiac is observed. What triggers the onset is still unknown.
So it’s not a childhood disease.
Role of genetics in diagnostics:
Negative HLA-DQ2/8 excludes the disease - so you can stop following up a certain patient if they were considered risky before.
. Helpful for identification in families, if a mother has it, kids can be checked for his/her alleles, if they are negative, no follow up
Positive means nothing since %40 of the population is positive anyway.
