117 - Coeliac Disease

Question 1

Definition of coeliac disease

Answer 1

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

Question 2

Prevalence of coeliac

Answer 2

Perhaps 1:100

Question 3

HLA type associated with increased risk of coeliac

Answer 3

HLA-DQ2, DQ8

Question 4

When can coeliac manifest?

Answer 4

Any time from early childhood to late adulthood

Question 5

Races most affected by coeliac disease

Answer 5

Europeans, Middle Eastern, North Indians

Question 6

Part of body affected by coeliac

Answer 6

Duodenum, jejunum, ileum

Question 7

Nutrients absorbed in duodenum and jejunum

Answer 7

Protein, fat, fat-soluble vitamins (A, D, E, K), glucose, iron, water-soluble vitamins (B, C, folic acid)

Question 8

Nutrients absorbed in ileum

Answer 8

Vitamin B12, bile acids (reabsorbed, go to liver)

Question 9

Effect of coeliac disease decrease of small intestine absorption

Answer 9

Lose bile acids in faeces, which causes osmotic diarrhoea.
Loss of absorption of fat-soluble vitamins.
Loss of iron absorption

Question 10

Name for semi-circular folds in duodenum

Answer 10

Valves of Kerkring

Question 11

Role of Valves of Kerkring

Answer 11

Increase SA of duodenum.

Covered in 1mm vili.

Question 12

Where in crypts do stem cells sit?

Answer 12

Above Paneth cell zone and below zone of proliferation

Question 13

Number of cells released by an individual crypt per day

Answer 13

~200-300 cells

Question 14

Effect of severe coeliac on crypts

Answer 14

Crypt hyperplasia and villus atrophy

Question 15

Structure that fat is absorbed into in villi

Answer 15

Lacteal (lymphatic vessel)

Question 16

Paneth cells

Answer 16

Secrete alpha-defensins.

These protect intestine against bacteria.

Question 17

Components of normal intestinal mucosa

Answer 17

Brush border, enterocytes, goblet cells, intraepithelial lymphocytes.
Below this:
Plasma cells, lymphocytes

Question 18

Where in the small intestine do proteases, endopeptidases, phospholipases (for digestion), etc sit?

Answer 18

In brush border.

Question 19

Proportion of CD8+ cells in epithelium of intestine

Answer 19

~ 1 to every 4 enterocytes

Question 20

Histology of GIT epithelium in advanced coeliac

Answer 20

Total villous atrophy.
Crypt hyperplasia.
Intraepithelial lymphocytosis (marked increase in intraepithelial lymphocytes, plasma cells)

Question 21

Way to stage development of villous atrophy

Answer 21

Marsh types

Question 22

Marsh type 1

Answer 22

Villous:crypt ratio is normal (4:1), but there are more than 30 intraepithelial lymphocytes per 100 enterocytes).

Infiltrative.

Question 23

Marsh type 2

Answer 23

In Marsh type 2, in addition to intraepithelial lymphocytosis there is elongation and branching of crypts.

Hyperplastic.

Question 24

Marsh type 3

Answer 24

In Type 3, the villi are shortened and blunted and
the villous to crypt ratio is less than 1:4.

Destructive.

Question 25

What does villous:crypt ratio describe?

Answer 25

Ratio of relative number of mature absorptive enterocytes per unit area covering the villi to crypt number.

Question 26

Things that can cause intraepithelial lymphocytosis and villous atrophy with crypt hyperplasia (other than coeliac) 
1
2
3
4
5

Answer 26

• Tropical sprue
• Small bowel bacterial overgrowth
• Common variable immunodeficiency
• Autoimmune enteropathy
• Drugs – colchicine, vincristine, neomycin,
mycophenolate mofetil

Question 27

How does coeliac present?
1
2
3
4
5
6
7

Answer 27

• 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

Question 28

Four elements of pathogenesis of coeliac disease

Answer 28

• Genetics
• Environment
• T-cells
• Gluten

Question 29

Proportion of coeliac cases with either DQ2 or DQ8

Answer 29

99.6%

Question 30

Environmental factors in development of coeliac
1
2
3

Answer 30

1) Breast feeding is protective
2) Timing/amount of gluten introduced in infant diet increases risk
3) Infections (EG: gastro)

Question 31

Cytokine released by CD4+ T cells in coeliac

Answer 31

IFNg

Question 32

Amino acid component of gliadins that confers resistance to digestion

Answer 32

High proline content confers resistance to digestion by gastric, pancreatic, intestinal enzymes.

Question 33

Amino acid component of gliadins that makes them an effective antigen

Answer 33

Glutamine (gluten proteins are high in glutamine).

Question 34

Alteration that makes gluten very antigenic

Answer 34

Glutamine deamination by tissue transglutaminase, converting to negatively-charged glutamate

Question 35

Why does glutamate content make glutens more antigenic?

Answer 35

Negatively charged glutamate at position 4, 6, 7 can bind to HLA DQ2.
Present on MHCII to CD4+

Question 36

Effect of plasma cell activation on coeliac disease

Answer 36

No effect on intestinal mucosa.

Useful marker for status of coeliac disease (antibodies in the blood).

Question 37

Innate immune response to injury or infection of enterocytes
1
2
3
4

Answer 37

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

Question 38

Role of innate immune system in coeliac
1
2
3
4

Answer 38

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

Question 39

Serological testing of coeliac disease
1
2

Answer 39

1) Tissue transglutaminase antibody (90% sensitive, very specific)
2) Deamidated gliadin peptide (80-90% sensitivity)

Often perform these two tests together

Question 40

Ways to diagnose coeliac
1
2
3

Answer 40

1) Serology
2) HLA-DQ haplotyping (absence of DQ2, DQ8 effectively rules out coeliac diagnosis)
3) Small bowel biopsy (gold standard)

Question 41

Dangers of untreated coeliac disease
1
2
3 a, b, c, d

Answer 41

• 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