301 Coeliac Disease Flashcards
Symptoms of coeliac disease
Bloating, diarrhoea, nausea, flatulence, constipation, tiredness, headaches, sudden weight loss, hair loss, anaemia, osteoporosis, rash (dermatitis herpetiformis), neurological disorder
What can coeliac disease lead to?
Kidney & liver disease
Mortality rate in untreated coeliac disease
Factor 1.9-3.8
Caused by link to malignancies
What is gluten?
2 proteins: gliadin & glutenin
2 similar proteins in barley (hordeins) and rye (secalins)
10% wheat made up of gluten
What is gluten involved in?
Starch storage in cell
How much gluten can coeliac suffers tolerate?
20ppm so food must contain less than this to be “gluten free”
Coeliac disease immune response to gluten:
Trigger
Immune activation
Antibodies
Result
Treatment
- Gluten (from wheat, barley, rye) ingested
- Modified gluten peptides trigger T cells
- B cells produce anti-tTG and anti-gliadin antibodies
- Inflammation damages intestinal villi, leading to malabsorption
- Lifelong gluten-free diet
How does immune response occur with gluten in coeliac disease?
T cells react with gluten peptides, especially gliadin), which has been modified by enzyme tissue transglutaminase (tTG)
B cells produce antibodies against gluten and tTG, resulting in inflammation
Genetic predisposition for coeliac disease and immune response
People with genetic predisposition carry HLA-DQ2 or HLA-DQ8 genes which these T cells recognise gluten as a threat, becoming activated and launches immune response
What is the mechanism of CD4 T-cell response to gliadin in coeliac disease?
Tissue transglutaminase (tTG) deamidates native peptides, creating modified peptides
These presented by DQ2/DQ8 on antigen-presenting cells, activating CD4 T-cells
Activation leads to interferon-γ release causing destructive intestinal lesions
How does gluten trigger the immune response in coeliac disease?
Gluten-derived gliadin modified by tTG & presented by HLA-DQ2/8 on antigen-presenting cells
Activates T cells releasing IFNγ and promotes IL-15 expression
IL-15 stimulates NK-like cells to target intestinal cells, causing villi loss, crypt elongation & increased intraepithelial lymphocytes (IELs)
B cells produce antibodies against gliadin, endomysium & tTG
Coeliac sufferers and their genetics
All have HLA-DQ2 (90%) or DQ8 genes (10%)
MHC II molecules binds negatively charged peptides
Gluten not negatively charged but can be deamidated by tTG
Gluten is proline rich so not digested well
A deamidated 33mer binds to MHC with high affinity
Diagnosis of coeliac disease
Serum analysis for anti-gliadin/tTG antibodies
ELISA
Biopsy of intestine
HLA typing
Therapeutic agent: genetically modified gluten and MOA
Decreases gluten exposure by transamidation of gliadin
Therapeutic agent: zonulin inhibitor and MOA
Decreases zonulin secretion and inhibits intestinal permeability
Therapeutic agent: therapeutic vaccine and MOA
Creates immune tolerance to gluten fragments & desensitises coeliac disease patients to toxic effects of gluten
Therapeutic agent: probiotics and MOA
Detoxify gliadin & promote intestinal healing
Therapeutic agent: tissue transglutaminase inhibitors and MOA
Stop tissue transglutaminases from modifying gluten fragments, a process that otherwise triggers immune response
Aetiology of coeliac disease
- Genetics: genetic markers HLA-DQ2/8, 95% of people carry these genes are coeliac
- Environmental factors: gluten exposure, infections, early-life GI infections & gut microbiome imbalances
- Immune system dysregulation: with genetic predisposition consuming gluten, inflammation trigger
Nutritional implications: malabsorption
Damage to intestinal villi impairs nutrient absorption
Leads to vitamin deficiencies
Particularly if coeliac is untreated
Nutritional implications: vitamin and mineral deficiencies
- Iron: iron-deficiency anaemia due to impaired absorption which can lead to fatigue & weakness
- vit B: folate, B12 & B6 affecting energy levels, nerve function & RBC production
- Calcium & vit D: osteoporosis or osteopenia
- Zinc and Mg: affecting immune & muscle function
Nutritional implications: weight loss or growth issues
Children with untreated coeliac may experience stunted growth or delayed therapy
Adults may experience weight loss, weakness or muscle wasting
Nutritional implications: fat malabsorption
Damage to intestine leads to difficulty absorbing fats
Leads to fat-soluble vitamin deficiencies (A, D, E, K) and symptoms like diarrhoea & steatorrhoea
Nutritional implications: increased risk of lactose intolerance
Damage to intestinal lining may lead to 2ndary lactose (which digests lactose) is reduced when villi compromised
Nutritional implications: risk of additional health conditions
Prolonged nutrient deficiencies can increase risk of anaemia, osteoporosis, neurological disorders and fertility issues
