Coeliac Disease

Coeliac disease is a condition where an immune response to gluten causes inflammation of the small bowel mucosa. Withdrawal of gluten from the diet improves symptoms.

Pathophysiology

1.    Gluten is a type of protein found in wheat, rye and barley. Gluten itself is made up of several peptides including a class of proteins called gliadins.

2.    Genetics also play a role in coeliac disease, specifically the HLA-DQ2 and HLA-DQ8 alleles. These alleles code for major histocompatibility complex II proteins which are expressed by antigen presenting cells in the small intestine e.g. dendritic cells.

3.    Once gliadin reaches the small intestine it is taken up by enterocytes and transported into the lamina propria of the small bowel. Several theories exist to explain how this happens, two of which include:

• Paracellular Route: Zonulin is a protein that is responsible for regulating tight junctions between the cells in the digestive tract. Zonulin expression has been found to be amplified in patients with coeliac disease. This leads to increased mucosal permeability, thus allowing gliadin to pass into the lamina propria of the small bowel.^[i]
   
• Secretory IgA: Gliadin can also be transported to the lamina propria by binding to secretory IgA (sIgA).
   

4.    Patients with coeliac disease have high levels of tissue transglutaminase (TTG), an enzyme which deamidates gliadin into glutamic acid, or causes cross-linking of gliadin.

5.    The deamidation or cross-linking of gliadin increases the likelihood of these gluten peptides being bound by HLA-DQ2 or HLA-DQ8 which will be expressed by antigen presenting cells like dendritic cells.

6.    Antigen presenting cells will present these antigens to CD4+ T cells, specifically T-helper 1 cells. In response to this, activated CD4+ T cells will release inflammatory cytokines such as interferon-gamma and IL-1, which ultimately results in apoptosis of enterocytes.^[ii]

TL;DR Gluten has proteins that can cause inflammation and destruction of enterocytes in the small bowel, which results in malabsorption and the signs and symptoms seen in coeliac disease.

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Pathophysiology of Coeliac Disease

Histopathology

• Villous Atrophy: The villi of the small intestine are atrophied i.e. shorter in coeliac disease due to the destruction of enterocytes. The mucosa can also appear flat.
• Crypt Hyperplasia: The crypts between villi of the small intestine become larger and elongated. This may be due to the need for more enterocytes due to increased cell turnover which leads to the proliferation of stem cells.^[iii]
• Intraepithelial T Lymphocytes: Lymphocytes can be seen in the enterocytes. ^[iv]
• Inflammatory cells in the Lamina Propria: Lymphocytes can also be seen in the lamina propria.

Ed Uthman from Houston, TX, USA, CC BY 2.0 , via Wikimedia Commons

Section of the Small Bowel showing loss of normal villous architecture

Clinical Features

Asymptomatic

• Abdominal Pain
• Diarrhoea
• Bloating
• Acid reflux
• Malabsorption
  • Steatorrhoea: Oily stools from lack of fat absorption
  • Weight loss
  • Iron deficiency anaemia
  • Megaloblastic anaemia: Lack of vitamin B12/folate absorption (remember B12 is absorbed in the terminal ileum i.e. the small bowel)
• Malaise
• Fatigue
• Oral aphthous ulcers
• Dermatitis herpetiformis: A blistering and often itchy rash which appears on the abdomen
• Peripheral neuropathy/Ataxia: These are rarer symptoms of coeliac disease

Differential Diagnosis

• Inflammatory bowel disease
• Irritable bowel syndrome
• Diverticulitis
• Gastrointestinal malignancy

Risk Factors

• Autoimmune Conditions: T1DM, Thyroid disease, Autoimmune hepatitis
• Family history
• Down’s syndrome or Turner’s syndrome

Investigations

Bloods

• FBC: Iron deficiency anaemia/megaloblastic anaemia so look at haemoglobin and MCV.
• Iron studies: Ferritin can be low
• Coeliac serology: Patients should have been consuming gluten for 6 weeks prior to have these blood tests
  • First line:
    • Total serum IgA Antibody levels
    • Transglutaminase (TTG) Antibodies
  • Second line: If the first-line tests cannot be done or are weakly positive
    • Endomysial (EMA) Antibodies

Some patients may have IgA deficiencies (characterised by a low total IgA). TTG and EMA are both IgA antibodies, so they might be negative even though someone has coeliac disease. In this case, the following tests can be done:

• IgG TTG
• IgG EMA
• IgG Deamidated Gliadin Peptide Antibody (DGP)^[v]
   

Genetic Testing

HLA-DQ2 or HLA-DQ8 genetic testing can also be performed, the former being positive in close to 95% of patients with coeliac disease. These are not typically used in non-specialist settings.
 

Endoscopy and Biopsy

A small bowel biopsy is the gold-standard diagnostic method. Classic histological features will confirm the diagnosis. The British Society of Gastroenterologists recommend that at least 4 biopsies be obtained, with at least one being from the duodenal bulb.^[vi] Patients must be on a gluten containing diet during the time of the biopsy.

Management

A gluten free diet is crucial in patients with coeliac disease since gluten is so damaging for the small bowel. Thus, products such as bread, flour, pasta, crackers, pastries, cereals etc will need to be eliminated from the diet. Anti-tTG and anti-EMA titres correspond to disease severity and can therefore be used to monitor response to gluten eradication.

If a patient has severe dermatitis herpetiformis, they may require dermatology referral.

Complications

• Osteoporosis: Due to calcium malabsorption. Patients may require DEXA scanning in order to monitor bone mineral density.
• Enteropathy Associated T Cell Lymphoma:  Small, risk of developing a gastrointestinal T cell lymphoma
• Hyposplenism: Patients have a ‘functional hyposplenism’ i.e. the hyposplenism is due to excessive loss of lymphocytes which are being used in the gastrointestinal tract.^[vii] The spleen itself is not anatomically small. Patients may require pneumococcal vaccinations on a prophylactic basis.
• Nutrient Deficiency: Folate, iron, vitamin B₁₂ and calcium deficiencies can occur

References

^[i] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. [internet]. 2012. [cited 26^th August 2019]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384703/

^[ii] Sabatino AD, Corazza GR. Coeliac disease. [internet]. 2009. [cited 26^th August 2019]. Available from: https://www.sciencedirect.com/science/article/pii/S0140673609602543

^[iii] Young B, O’Dowd G and Woodford P. Wheater’s Functional Histology. 6e. Elsevier Ltd. 2014.

^[iv] Pathology Outlines. Celiac sprue. [internet]. 2019. [cited 26^th August 2019]. Available from: http://www.pathologyoutlines.com/topic/smallbowelceliacsprue.html

^[v] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC130112/

https://cks.nice.org.uk/topics/coeliac-disease/diagnosis/assessment/

https://www.bsg.org.uk/wp-content/uploads/2019/12/BSG-guidelines-on-the-diagnosis-and-management-of-adult-coeliac-disease.pdf

^[vii] Medscape. Risk of Morbidity in Contemporary Celiac disease. [internet]. 2010. [cited 30^th August 2019]. Available from: https://www.medscape.com/viewarticle/734493_10