Coeliac disease

Question 1

What is coeliac disease?

Answer 1

Gluten-sensitive enteropathy
Small intestinal villous atrophy that resolves when gluten is withdrawn from the diet

Inappropriate T cell-mediated immune response in genetically susceptible individuals

α-gliadin is most toxic moiety

Malabsorptive illness with steatorrhoea affecting children and adults

Question 2

Describe the epidemiology of coeliac disease

Answer 2

 Autoimmune condition
 Females > Males
 Can present at any age
o However, 20% of patients are over 60 years old at diagnosis
 Prevalence 1% UK
- genetic link

Question 3

Describe the genetic link in coeliac disease

Answer 3

 10% prevalence in 1 st degree relatives

 95% are HLA-DQ2 (rest are HLA-DQ8)

Question 4

What is the infectious hypothesis?

Answer 4

 Infection with Adenovirus 12 in genetically susceptible individuals has been suggested as a trigger
 The peptide on α-gliadin is similar to that within E1b portion of the virus
o Gliadins andgluteninsare the two main components of the gluten fraction of the wheatseed
 Leads to cross reactivity with α-gliadin, and the development of coeliac disease

Question 5

What is the action of α-gliadin in coeliac disease?

Answer 5

 Digestion of α-gliadin (in gluten) produces a stable peptide
 Gliadin peptides are resistant to human proteases  able to persist intact in the small intestinal lumen
 This is absorbed intact into the lamina propria (mechanism unknown)
 In the intestinal submucosa these peptides trigger both innate and adaptive immune activation
 In the submucosa, gluten peptides are exposed to tissue transglutaminase (from damaged epithelium)
o leads to deamination of glutamine residues by tTG
o tTG is an enzyme normally involved in collagen cross-linking and tissue remodelling.
o tTG is the tissue autoantigen in coeliac disease

Question 6

What does deamination of glutamine residues by tTG result in?

Answer 6

1) high-affinity binding to coeliac-associated HLA peptides

2) activation of helper T (Th) cells.

Question 7

What is the effect of deamination in relation to antigen presenting cells?

Answer 7

high-affinity binding to coeliac-associated HLA peptides (DQ2 or DQ8) found on antigen-presenting cells
o tTG covalently links itself to gliadin peptides
o The resulting structure can be presented by APC (with the same gliadin recognizing DQ isoforms)
to T-cells
o NB: For this reason, people must carry either HLA-DQ2 (95% of patients with coeliac disease) or
HLA-DQ8 (5% of patients with coeliac disease) to develop coeliac disease.

Question 8

What is the effect of deamination on the activation of helper T cells?

Answer 8

cells.Causes pro-inflammatory T-cell response:
o Th1 T c  induce cell death and tissue remodelling with villous atrophy and crypt hyperplasia
o Th2  trigger plasma cell maturation - anti-gliadin and anti-tTG antibody production

Question 9

How doe infants present with coeliac disease?

Answer 9

 Presents aged 4-24 months (after cereals have been introduced)
 Impaired growth, diarrhoea, vomiting, abdominal distension

Question 10

How do older children present with coliac disease?

Answer 10

Anaemia, short stature (up to 8%), pubertal delay, recurrent abdominal pain or behavioural disturbance

Question 11

What is the presentation of adults with coeliac disease

Answer 11

• symptomatic
  o diarrhoea, bloating, flatulence, abdominal discomfort
  o 50% have no history of diarrhoea, may be constipated
  o Symptomatic disease may be provoked by infection, pregnancy or surgery
• Chronic or Recurrent IDA
• Nutritional deficiency
• Reduced fertility/amenorrhoea
• Osteoporosis
• Unexplained isolated ↑ AST/ALT
• Neurological /psychiatric symptoms

Question 12

Briefly describe the absorption/digestion features of the duodenum and proximal jejunum

Answer 12

o Digestion > absorption
o Acidic pH increases the solubility and absorption of
polyvalent cations (e.g. Iron and Calcium)

Question 13

Briefly describe the absorption/digestion features of the distal jejunum and ileum

Answer 13

o Responsible for bulk of nutrient absorption
o Terminal ileum → specialised absorption of cobalamin
(Vitamin B12) and Bile Salts

Question 14

Briefly describe the absorption/digestion features of the colon

Answer 14

o Salvages fluid and electrolytes not absorbed by the SI
o Absorbs short chain fatty acids produced by colonic bacteria from undigested carbohydrates

Absorbs approximately 6 litres of fluid daily
o Alongside fat, protein and electrolytes

Question 15

How is the absorptive capacity of the small bowel made possible?

Answer 15

o Surface folding
(valvulae conniventes)
o Villi
o Microvilli

Question 16

What are the pathological findings of coeliac disease?

Answer 16

Mucosal inflammation can vary in severity and extent
 Mild proximal disease typically occurs
 Mucosal damage may be patchy
 Characterised by loss of villous height and inflammatory
infiltrate
o Results in loss of surface area
 Villi may be completely flat or short and broad (sub-total
villous atrophy)
 No change in total mucosal thickness as crypts become
elongated (hypertrophy)
 Increased plasma cells and intraepithelial lymphoctyes (IELs)

Question 17

How may the small bowel cause symptoms in disease?

Answer 17

 Diarrhoea
o watery and high volume (reduction in absorptive capacity)
o rarely bloody (bloody diarrhoea is normally from colon)
o Steatorrhoea  the excretion of abnormal quantities of fat with the faeces owing to reduced
absorption of fat by the intestine
 Malabsorption (Fat/Vits/Carbs/Protein)
 Weight loss
 Abdominal pain/vomiting

Question 18

What are indicators of small bowel disease?

Answer 18

 Malabsorption/electrolyte imbalances:
o Folate
o Ca/Vit D = increases risk of osteoporosis
o Vit K/coagulopathy
o Magnesium
o Vitamin B12 (rarely occurs in coeliac disease because B12 is absorbed in the terminal ileum)
 Coeliac disease predominantly affects the duodenum
 Chronic or Recurrent IDA

Question 19

Describe iron absorption in the gut

Answer 19

 Iron absorption occurs predominantly in the duodenum and upper jejunum
 At physiological pH, ferrous iron (Fe 2 +) is rapidly oxidized to the insoluble ferric (Fe 3+ ) form
 Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron
 Enhanced by ascorbic acid (vitamin C), citric acid but inhibited by phytates and tannins (tea)

Question 20

How is coeliac disease diagnosed?

Answer 20

Serology – IgA tTG (Tissue Transglutaminase Antibodies)

IgA EMA (antiendomysial Ab)

In adults TTG is more sensitive, EMA is more specific

Question 21

How can compliance of a gluten free diet be monitored

Answer 21

Seroconversion with gluten free diet (GFD) – can be used to monitor compliance
o tTG becomes negative with GFD
o NB: people are changing to GFD for a number of other reasons, making it virtually impossible to
diagnose coeliac disease as they will already be TTG negative
o Must be on gluten rich diet for 4-6 weeks prior to test

Question 22

What are the features of coeliac disease found on endoscopy?

Answer 22

 Scalloping of the folds
 Paucity of folds
 Mosaic pattern ('cracked-mud‘)
 Prominent submucosal blood
vessels
 Nodular pattern to the mucosa

Question 23

How can coeliac disease be classed and severity graded

Answer 23

MARSH classification, based on intraepithelial lymphocytes, crypts and villi

Question 24

What are the differential diagnoses for coeliac disease?

Answer 24

Villous atrophy but negative coeliac serology
o Check IgA – selective deficiency in 2-5%
 Can be a reason why the blood test is negative in some patients (false negative)
 IgG antibody test can be carried out in patients with low IgA titre

Rarer causes:
o Giardiasis, CVID, Radiation enteritis, Crohn’s disease, Lymphoma, Whipple’s disease, Tropical
Sprue, HIV enteropathy, chronic ischaemia, NSAIDs

Question 25

What is giardiasis?

Answer 25

 Most common parasitic infection in humans
 Caused by infection with Giardia lamblia
 Causes villus atrophy

Question 26

What are the coeliac-associated diseases?

Answer 26

o Dermatitis Herpetiformis
o T1DM
o Thyrotoxicosis
o Addison’s disease

Question 27

What is dermatitis herpetiformis

Answer 27

o Causes intensely itchy rash on extensor surfaces
o Gluten sensitive
o 90% villous atrophy
o Treatment = GFD and Dapsone (for rash)
 Sulfone antibiotic

Question 28

Describe the gluten free diet

Answer 28

 Avoid – Wheat, Barley and Rye
 Can eat –Rice, Maize and Oats (NB: may be cross-contaminated with wheat and rye)
 Symptomatic improvement in 70% within 2 weeks
 Continue dairy (50% experience secondary hypolactasia – lactose intolerance)
o Villus atrophy causes loss of lactase (BBE) activity
o Activity does not return until villus atrophy has been resolved
 85% respond (histology takes 3-12 months)
 2 nd biopsy and re-challenge rarely required in adults

Question 29

What are the complications of coeliac disease?

Answer 29

 Increased infection rate
 Osteoporosis
 Refractory Coeliac Disease
 Increased risk of malignancy

Question 30

What is the link between coeliac disease and infections?

Answer 30

 Patients with coeliac disease experience functional hyposplenism
o Howell-Jolly bodies are typically seen
 Risk of infection with:
o Encapsulated organisms
o Pneumococcal
o Haemophilus influenzae
o Meningococcus
 Vaccination against these infections is key

Question 31

What is the link between coeliac disease and osteoporosis?

Answer 31

 25% of coeliac patients Vs. 5% matched controls
o Low BMI (= risk factor for OP)
o Calcium/Vit D deficiency
 Consider DEXA at diagnosis
o Potentially wait 6 months to 1 year before DEXA to allow for nutritional recovery
o At this point the bone density will be much a more accurate representation for years ahead
 Adequate Calcium/Vit D intake/supplementation

Question 32

What is refractory coeliac disease?

Answer 32

recurrent malabsorptive symptoms and villous atrophy despite strict
adherence to a gluten-free diet (GFD) for at least 6-12 months in the absence of other causes of
nonresponsive treated coeliac disease and overt malignancy
o Occurs in less than 5% of coeliac patients

Question 33

What are the two types of refractory coeliac disease?

Answer 33

• RCD I

- RCD II

Question 34

Describe RCD I

Answer 34

persistent villous atrophy but normal immuno-phenotype
o 96% 5-year survival
o These patients have ongoing inflammation in small bowel
o Rx: Steroids/Azathioprine (>75% response)  immune supression
 Generally a good response

Question 35

Describe RCD II

Answer 35

persistent villous atrophy with abnormal immunophenotype (CD3/CD8 negative)
o Can develop ulcerative jejunitis - ulceration in jejunum/ileum
o 58% 5-year survival
o 60-80% progression to Enteropathy-associated T cell Lymphoma (EATL) @ 5y

Question 36

What are the coeliac related malignancies?

Answer 36

• Enteropathy-associated T-cell Lymphoma (EATL)
• Small Bowel Adenocarcinoma
• Oesophageal and colonic adenocarcinoma