117 - Coeliac Disease Flashcards
Definition of coeliac disease
Immunologically mediated disease in genetically susceptible individuals, driven by an environmental antigen, gluten found in wheat, rye and barley, which results in
chronic inflammation of the small bowel mucosa
Prevalence of coeliac
Perhaps 1:100
HLA type associated with increased risk of coeliac
HLA-DQ2, DQ8
When can coeliac manifest?
Any time from early childhood to late adulthood
Races most affected by coeliac disease
Europeans, Middle Eastern, North Indians
Part of body affected by coeliac
Duodenum, jejunum, ileum
Nutrients absorbed in duodenum and jejunum
Protein, fat, fat-soluble vitamins (A, D, E, K), glucose, iron, water-soluble vitamins (B, C, folic acid)
Nutrients absorbed in ileum
Vitamin B12, bile acids (reabsorbed, go to liver)
Effect of coeliac disease decrease of small intestine absorption
Lose bile acids in faeces, which causes osmotic diarrhoea.
Loss of absorption of fat-soluble vitamins.
Loss of iron absorption
Name for semi-circular folds in duodenum
Valves of Kerkring
Role of Valves of Kerkring
Increase SA of duodenum.
Covered in 1mm vili.
Where in crypts do stem cells sit?
Above Paneth cell zone and below zone of proliferation
Number of cells released by an individual crypt per day
~200-300 cells
Effect of severe coeliac on crypts
Crypt hyperplasia and villus atrophy
Structure that fat is absorbed into in villi
Lacteal (lymphatic vessel)
Paneth cells
Secrete alpha-defensins.
These protect intestine against bacteria.
Components of normal intestinal mucosa
Brush border, enterocytes, goblet cells, intraepithelial lymphocytes.
Below this:
Plasma cells, lymphocytes
Where in the small intestine do proteases, endopeptidases, phospholipases (for digestion), etc sit?
In brush border.
Proportion of CD8+ cells in epithelium of intestine
~ 1 to every 4 enterocytes
Histology of GIT epithelium in advanced coeliac
Total villous atrophy.
Crypt hyperplasia.
Intraepithelial lymphocytosis (marked increase in intraepithelial lymphocytes, plasma cells)
Way to stage development of villous atrophy
Marsh types
Marsh type 1
Villous:crypt ratio is normal (4:1), but there are more than 30 intraepithelial lymphocytes per 100 enterocytes).
Infiltrative.
Marsh type 2
In Marsh type 2, in addition to intraepithelial lymphocytosis there is elongation and branching of crypts.
Hyperplastic.
Marsh type 3
In Type 3, the villi are shortened and blunted and
the villous to crypt ratio is less than 1:4.
Destructive.
What does villous:crypt ratio describe?
Ratio of relative number of mature absorptive enterocytes per unit area covering the villi to crypt number.
Things that can cause intraepithelial lymphocytosis and villous atrophy with crypt hyperplasia (other than coeliac) 1 2 3 4 5
• Tropical sprue • Small bowel bacterial overgrowth • Common variable immunodeficiency • Autoimmune enteropathy • Drugs – colchicine, vincristine, neomycin, mycophenolate mofetil
How does coeliac present? 1 2 3 4 5 6 7
• Gastrointestinal: diarrhoea, bloating, abdominal
cramps, flatulence
• Anaemia (iron deficiency), vitamin deficiencies
• Malabsorption of nutrients
• Failure to thrive as an infant
• Osteoporosis
• Lethargy (chronic fatigue), migraines, infertility (in women),
mouth ulcers
• Increased prevalence of autoimmune diseases
– e.g. Type I diabetes, autoimmune thyroiditis
• Can be completely asymptomatic
Four elements of pathogenesis of coeliac disease
- Genetics
- Environment
- T-cells
- Gluten
Proportion of coeliac cases with either DQ2 or DQ8
99.6%
Environmental factors in development of coeliac
1
2
3
1) Breast feeding is protective
2) Timing/amount of gluten introduced in infant diet increases risk
3) Infections (EG: gastro)
Cytokine released by CD4+ T cells in coeliac
IFNg
Amino acid component of gliadins that confers resistance to digestion
High proline content confers resistance to digestion by gastric, pancreatic, intestinal enzymes.
Amino acid component of gliadins that makes them an effective antigen
Glutamine (gluten proteins are high in glutamine).
Alteration that makes gluten very antigenic
Glutamine deamination by tissue transglutaminase, converting to negatively-charged glutamate
Why does glutamate content make glutens more antigenic?
Negatively charged glutamate at position 4, 6, 7 can bind to HLA DQ2.
Present on MHCII to CD4+
Effect of plasma cell activation on coeliac disease
No effect on intestinal mucosa.
Useful marker for status of coeliac disease (antibodies in the blood).
Innate immune response to injury or infection of enterocytes 1 2 3 4
1) Infection of an epithelial cell induces synthesis of heat-shock proteins (stress related)
2) Infected epithelial cell expresses MIC-A, MIC-B (atypical class I molecules)
3) Gamma/delta T cells with NK receptor NKG2D binds MIC-A and MIC-B.
4) This induces apoptosis in target epithelial cell
Role of innate immune system in coeliac 1 2 3 4
1) Gliadin peptides can stress epithelial cells
2) Stressed epithelial cell releases IL-15, which lowers TCR activation threshold, causes intraepithelial lymphocytes to become autoreactive, proliferate.
3) IELs induced to express NKG2D, release IFNg.
4) IELs use NKG2D to make epithelial cells undergo apoptosis
Serological testing of coeliac disease
1
2
1) Tissue transglutaminase antibody (90% sensitive, very specific)
2) Deamidated gliadin peptide (80-90% sensitivity)
Often perform these two tests together
Ways to diagnose coeliac
1
2
3
1) Serology
2) HLA-DQ haplotyping (absence of DQ2, DQ8 effectively rules out coeliac diagnosis)
3) Small bowel biopsy (gold standard)
Dangers of untreated coeliac disease
1
2
3 a, b, c, d
• Long term risks if left untreated include: Osteoporosis Autoimmune diseases Increased risk of cancer – 20x relative risk for small bowel lymphoma (EATL) – 30x RR for small bowel adenocarcinoma – 2-4x RR for oesophageal cancer – 2x increased mortality
