Coeliac disease Flashcards
Prevalence of CD
- 1 in 100 in UK and EU
- Sahara: 1 in 14
- Sweden: 1 in 14
- Ireland 1 in 55
Definition of CD
gluten-sensitive enteropathy which causes inflammation of the bowel which leads to flattening of villi, elongated crypts and intra-epithelial lymphocytosis
Oslo terminology for CD: classical, non-classical, subclinical, potential CD, CD autoimmunity, genetically at risk
- classical: patients with signs and symptoms of CD (diarrhoea, steatorrhoea)
- non-classical: no signs or symptoms of malabsorption
- subclinical: have clinical/lab signs of malabsorption such as anemia or osteoporosis but no other symptoms
- potential CD: normal mucosa but risk of positive CD serology
- CD autoimmunity: no biopsy but positive for tissue transglutaminase
- genetically at risk: family members with CD or HLADQ2/DQ8 positive (2-20% risk)
Screening for CD
- use IgA and IgG1 (in case IgA deficient) tests for endomysium (needs experienced microbiologist as uses fluoroscopy) and anti-tissue transglutaminase (high throughput as uses ELISA testing)
- in adults use serology + biopsy
- in children, serology sufficient (if tTG is 10x normal)
Modified Marsh criteria for biopsy
0 = normal
1= intra-epithelial lymphocytosis
2= crypt hyperplasia
3 a) partial villous atrophy b) subtotal villous atrophy c) total villous atrophy
Mechanism of coeliac disease
1) gliadin and glutenins from gluten digested peptides cross into the lamina propria (unsure how this mechanism occurs)
2) tissue transglutaminase deamidated the gluten fragments (changes charges on AA) which means it is more recognised by dendritic cells and T cells
3) DQ2 dendritic cell presents the gluten antigen to gluten-sensitive T cell
4) T cells produces IFNy which activates plasma B cells to produce IgA and IgG, fibroblasts to produce matrix-metalloproteases 1 and 3 which degrade the collagen matrix and leads to vollious blunting, recruitment of cytotoxic T cells which degrade the lamina propria
5) this causes an increase in intra-epithelial lymphocytes: the more aggressive alpha-beta T cell receptor lymphocytes produce further IL15 and IFNy which propagates inflammatory effect
The potential role of the microbiota in CD
- CD patients have lower levels of lactobacilli and bifidobacteria
- they have higher levels of bacteriocides and other gram-negative bacteria
- single case studies have suggested that FMT for refractory coeliac disease with C.Diff has led to reversal
Genetics and coeliac disease
- HLA DQ2/8 accounts for 30% of heritability (but 40% of the population have this)
- GWAS have confirmed 14 new genes involved in CD, where functions are in: co-activation or inhibition of T cells, T cell maturation in the thymus, cytokine/chemokine signalling, innate detection of viral RNA (suggests role of the microbiota)
Associated diseases with CD
SLE, sjogrens syndrome, T1DM, Addison’s, T1DM, autoimmune thyroid disease, dermatitis herpetiformis (blistering rash on elbows and knees)
Prognosis of CD: standardised mortality ratios
- diagnosed: 2
- undiagnosed: 6
- late diagnosis: 3.8
Treatment for CD including response rates and refractory coeliac, and issues with the diet
- gluten-free diet (20 ppm or 10mg/100g): 70% respond. Of the 30% who don’t, some question over their compliance with the diet or may be underlying small bowel bacterial overgrowth
- some may need to also avoid oats (cross-reactivity with the avenin proteins in the oats)
- quinoa ok for some (good as contains a lot of fibre, folate, B12, iron, Mg which CD low in) but some do show some cross-reactivity as protein structure is similar to gluten
- may also have cross-reaction between families: may need different toaster, different butter etc
- refractory coeliac is rare (~1 per 1,000,000) but may lead to T cell lymphoma
- however diet has low palatability and is expensive, there are also some issues that there is no international consensus over what constitutes ‘GF’ which may make travelling difficult
Novel treatment options for CD
- trying to ‘tighten’ tight junctions so gluten cannot get through
- changing epitope structure so not recognised- although laborious
- using bacterial enzymes to break down gluten to <12 AA so not recognised by dendritic cell
- inhibition of tissue transglutaminase
- reducing inflammatory cytokines with biologic agents
- desensitisation of gluten using vaccines or intra-nasal sprays
Complications of CD
- long-term malabsorption and osteoporosis
- leads to T1DM, autoimmune thyroid disease
- refractory coeliac disease: ulcerative jejunitis, enteropathy-associated T cell lymphoma. Key problem with refractory coeliac disease seems to be the intra-epithelial lymphocytes
Non-coeliac gluten sensitivity definition
- sensitivity to gluten that is between IgA (CD) and IgG (wheat allergy) mediated disease
- increased intestinal permeability
- 50% are HLA DQ2/8 positive
- involvement from the innate immune system
Key components of wheat: PRO, CHO, lipids
- PRO: alpha amylase trypsin (natural pesticide, 10-20% wheat PRO), gliadin, glutenins, avenins
- CHO: some indigestible which are good pre-biotics, but high in FODMAPs
- Lipid: content thought to be pro-inflammatory
