Coeliac disease
Definition
Autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward
While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy.
Risk Factors
Almost all coeliac patients have specific HLA alleles:
HLA-DQ2 common in Europe (95%)
HLA-DQ8 more common in Middle East
But both have very low penetrance
Autoimmune thyroid disease
IgA deficiency
Hypothetical factors:
timing of initial gluten exposure
type 1 diabetes
gastrointestinal infection leading to gluten antigen mimicry
Infection by rotavirus[45] or human intestinal adenovirus??
direct damage to the intestinal-epithelial barrier leading to abnormal exposure of the mucosa to gluten peptides
Differential diagnosis
Peptic duodenitis
Small-intestinal bacterial overgrowth
Post-gastroenteritis
Eosinophilic enteritis
CVID and other immunodeficiency states
Autoimmune enteropathy
Chronic pancreatitis
Hypolactasia
Whipple's disease
Epidemiology
Prevalence between 1 in 67 and 1 in 250 with an approximate average of 1%
North and South America, eastern and western Europe, Turkey, the Middle East, and North Africa
Far less common in people from southeast Asia and sub-Saharan Africa
Men and women are roughly equally affected
But women tend to make up almost two-thirds of patients
First peak period of presentation is in infancy soon after the initial exposures to gluten
Second, larger peak in the fourth and fifth decades
Most common age at diagnosis in the US is about 40 years
Aetiology
Reaction to prolamins
Autoimmune reaction leads to a truncating of the villi lining the small intestine (villous atrophy)
This interferes with the absorption of nutrients
Clinical features
Primary:
Pale, voluminous and malodorous diarrhoea
Abdominal pain and cramping (colicky)
Bloatedness with abdominal distension
A degree of lactose intolerance
Malabsorption-related:
Nutients, minerals and the fat-soluble vitamins A, D, E, and K.[5][11]
=> weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy
folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia.
Calcium and vitamin D malabsorption
Compensatory secondary hyperparathyroidism
Abnormal coagulation due to vitamin K deficiency
Bacterial overgrowth of the small intestine
Can worsen malabsorption or cause malabsorption despite adherence to treatment.[12]
Other
Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition
Hyposplenism (a small and underactive spleen);[16]
Abnormal liver function tests
Pathophysiology
Reaction to gliadin, a prolamin found in wheat
Resistant to human proteases, allowing them to persist intact in the small intestinal lumen
Specifically to three peptides found in prolamins
Also to similar proteins found in the crops of the tribe Triticeae
includes other common grains such as barley and rye
Unknown how these peptides gain access to the lamina propria
Faulty tight junctions
Endothelial cell transcytosis
Sampling of the intestinal lumen by dendritic cells
Passage during resorption of apoptotic villous enterocytes
Gluten peptides stimulate interleukin-15 production by dendritic cells and macrophages
In the submucosa, gluten peptides are de-amidated by tissue transglutaminase (tTG)
Enzyme normally involved in collagen cross-linking and tissue remodelling
Allows for high-affinity binding to the coeliac-associated HLA peptides and activation of helper T (Th) cells. [15]
Stimulation of Th cells causes:
Cell death and tissue remodelling with villous atrophy and crypt hyperplasia (Th1-mediated)
Plasma cell maturation and subsequent anti-gliadin and anti-tTG antibody production (Th2-mediated). [16]
Link to IgA deficiency:
Lack of secretory IgA and Peyer patch malfunction allow for increased free gluten peptides in the submucosa??
Investigations
FBC and blood smear with iron studies
IgA-tTG ELISA
Endomysial antibody (EMA)
More expensive alternative to IgA-tTG with greater specificity but lower sensitivity
Based on immunofluorescence
Operator-dependent
IgG-tTG
Useful in people who are IgA deficient
Relatively common in coeliac
IgG DGP or IgA/IgG DGP (deamidated gliadin peptide)
Upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum
HLA typing??
cf penetrance issues
Not useful for diagnosis
Management
a) conservative
The only known effective treatment is a lifelong gluten-free diet.[5]
Adherence is difficult
Dietary changes may lead to deficiencies in fibre and other nutrients
There is substantial evidence that oats that are not contaminated by wheat or barley are safe for the vast majority of patients with coeliac disease.[B Evidence] [44] [45] [46]
In practice, oats should be avoided until the patient is in clinical remission
Then wheat-free oats may be gradually added to the diet
b) medical
Steroids?
A number of agents are under investigation
Unlikely to replace the gluten-free diet
May be used to allow for laxity in situations of low-level gluten exposure--for example, in food additives
c) surgical
Prognosis
Most, up to 90% in some studies, will have complete and lasting resolution of symptoms on a gluten-free diet alone
For the 10% with persistent symptoms, most of these will be attributed to ongoing gluten exposure, lactose intolerance, and irritable bowel syndrome
Hyposplenism
Less than 1% can be expected to develop refractory coeliac disease. [51]