L8 20 Mar 2019 Flashcards
Coeliac Disease
What is coeliac disease?
- immunological disease driven by an environmental antigen (gluten) found in wheat, rye and barley
- results in chronic inflammation of the small bowel mucosa
- main diagnosis/treatment: removal of gluten from diet
What are the risk factors for coeliac disease?
- dietary gluten
- HLA-DQ2/8 and other genes
- environmental factors
How is coeliac disease diagnosed?
- blood test: antibodies to transglutaminase and gliadin
- gastroscopy: small intestinal villous atrophy, crypt hyperplasia, raised intraepithelial lymphocytes
What is glutin?
- glutin = latin “glue”
- two main proteins: gliadin, glutenin
acute effects of glutin on coeliacs
- symptoms (within hours): vomiting, abdominal pain, diarrhoea, headache, lethargy
chronic effects of glutin on coeliacs
- symptons: nausea, bloating, pain, diarrhoea, constipation; chronic fatigue/lethargy, anaemia, nutrient deficiencies (e.g. low iron), weight loss, poor growth
- co-morbidities and increased mortality: autoimmune disease, lymphoproliferative malignancy, sepsis, osteoporosis, infertility, and obstetric complications, liver disease, neurological issues
- impaired quality of life + increased health related costs prior to diagnosis
Why is the gluten free diet no an easy treatment?
- lifelong, strict and complex
- safe threshold not well-defined (even a tiny amount of gluten can be harmful)
- costly and can be less palatable
- PAL statements are often confusing and rarely helpful
- labels can be tricky
Why is the gluten free diet not nutritionally superior?
- can be higher in starch, sugar, fat and calories
- high GI index
- lower in protein, iron and folate
- low in fiber
- problematic weight gain
- low gluten intake = higher chance of heart disease
main features of coeliac disease pathogenesis
- gluten: immunogenic regions resistant to gastrointestinal proteolysis - more proline = more problems
- genetics: presence of key susceptibility genes (HLA-DQ2 or HLA-DQ8)
-
immunity: gluten = post-translationally modified and becomes more immunogenic
- stimulates HLA-restricted CD4+ gluten-specific T-cells that have pro-inflammatory phenotype
- inflammatory cascade = villous atrophy
gluten-specific CD4+ T cell pro-inflammatory response
- antigen presenting cells see deaminated gliadin and (incorrectly) presents it to CD4+ cells
- T cell has an adverse reaction = release of cytokines (IFN-γ and IL21)
- cytokines send instruction to epithelium for destruction of gut epithelium = villi blunting
- antibody production
significance of post-translational modification of gluten for antigen binding to HLA
deamidation of gluten peptides = increased stability = harder to breakdown
What causes and mediates villous atrophy?
T cell activation important, but innate mechanisms facilitate intestinal destruction
- regulatory T cells change how Th1 (CD4+) cells produce IFN-γ and IL21
- IFN-γ signals to epithelial cells and resident CD8+ cells kills epithelial cells
screening tests to diagnose coeliac disease
- antibody tests (85-90% sensitive - detects in that percentage of coeliac patients)
- tissue transglutaminase antibody (tTG) (IgA)
- deamidated gliadin peptide (DGP) (IgG)
- definite diagnosis by gastroscopy
Why do some people lose gluten tolerance?
- infections (esp. in GIT - rotavirus)
- medications e.g. proton pump inhibitors
- seasonality
- higher socioeconomic status
- maternal iron supplementation/iron overload
- ? timing and amount of gluten in infancy
- ? elective caesarean section
- ? breast feeding
How does changes in the microbiome trigger coeliac disease?
- Children with CD: Pseudomonas > Lactobacilli (opposite in healthy)
- Germ free (gnotobiotic) mouse studies: Lactobacilli cleave gluten to reduce immunotoxicity vs. Pseudomonas, which cleaves at different residues to increase immunotoxicity of gluten
