Section 1: Epidemiology and aetiology
Coeliac disease (CD) is a common GI disease characterised by small bowel mucosal injury and nutrient malabsorption in genetically susceptible individuals following dietary ingestion of gluten. Gluten is commonly found in wheat, rye and barley.
CD was first described by Dr Samuel Gee in 1888.1 The highest prevalence is in Ireland, Finland and countries to which Europeans have emigrated (North America, Australia).
CD is almost unknown in east Asia, where there is a lack of HLA-DR3, DQB1*0201 haplotype. However, the incidence is increasing in Africa (Sahrawi population),2 Asia (India, Pakistan)3 and the Middle East. Prevalence is 0.7-2% in most of these populations.4
The incidence of CD confirmed by biopsy ranges from two to 13 per 100,000 per year.4
The pathogenesis involves interactions between environmental, genetic and immunological factors.5
Proteins in wheat, rye and barley are collectively termed gluten. Wheat contains gliadins and glutenins. Barley and rye have hordeins and secalins that activate disease. The high glutamine and proline content in these proteins may play a key part in disease pathogenesis.6
CD is strongly associated with specific HLA class II genes that map to the DQ locus.7
CD pathogenesis is divided into three major series of events - luminal and early mucosal events, activation of pathogenic CD4+ T cells, and subsequent events leading to tissue damage. Some aspects are well understood, others remain the subject of continuing research.
The US National Institutes of Health (NIH) consensus classifies CD based on subphenotypes (see box 1).8
|Box 1: Classification of CD|
|Classification||Symptoms||Diagnoses based on|
|Classical CD||GI symptoms
Complications secondary to malnutrition
Symptoms improve on gluten-free (GF) diet
|CD with atypical symptoms||Extra-intestinal manifestations
Few or no GI symptoms
Symptoms improve on GF diet
|Silent CD||Asymptomatic||Positive serology
May develop symptoms or histological changes
No villous atrophy
Section 2: Making the diagnosis
No single test will establish the diagnosis. It is important to recognise the clinical features (see box 2); these and the laboratory findings may establish the diagnosis. All tests should be performed on a gluten-rich diet.
|Box 2: Clinical features|
Coeliac serology, the first step in diagnosis, involves IgA antihuman tissue transglutaminase (TTG) and IgA endomysial antibody immunofluorescence (EMA) tests. The sensitivity and specificity of EMA and TTG have been estimated as >95% and close to 100%, respectively.9
Endoscopy and biopsies
Endoscopy without biopsies is inadequate. If clinical suspicion is high, gastroscopy and duodenal biopsy should be performed, even if serology is negative.10,11 A presumptive diagnosis can be made with positive serology and suggestive biopsies, but this is confirmed when symptoms resolve on a GF diet.
If there is diagnostic uncertainty, HLA haplotype testing can be useful. More than 95% of affected patients have DQ2 (HLA-DQA1*05-DQB1*02) or DQ8 (HLADQA1*03-DQB1*0302), compared with 40% in the general population. CD is extremely unlikely if HLA-DQ2 or DQ8 is negative.12
Gluten challenge is rare; its most likely scenario is in patients who are on a GF diet despite not having been diagnosed with CD.
In patients with suggestive symptoms and negative serology, it is important to consider selective IgA deficiency and perform an IgG-TTG or IgG-EMA test, or genotyping.
Section 3: Managing the condition
Treatment of CD should be started only after a complete diagnostic evaluation. There is no currently available medication that can safely prevent the mucosal damage that occurs due to gluten exposure.
The only effective treatment is a lifelong GF diet. It is impossible to exclude all gluten, so for practical purposes, 'gluten-free' is minimal gluten that is harmless to the gut.
The Codex Alimentarius defines GF foods as having less than 20ppm of gluten. The 'safe' limit is likely to be about 10mg per day but anecdotal reports suggest some patients may be sensitive even to this amount.
The NIH consensus statement lists six key elements in the management of CD, similar to the NICE guidelines. They can be summarised as CELIAC (Consultation with a skilled dietitian, Education, Lifelong adherence to GF diet, Identification and treatment of nutritional deficiencies, Access to an advocacy group, Continuous long-term follow-up).8
Following a GF diet requires specific education from a specialist dietitian. Self-education and identifying gluten-containing products should also be encouraged.
Physicians should consider the possibility of, and treat, vitamin and mineral deficiencies.
Patients should be encouraged to join Coeliac UK or an equivalent organisation.
There has in the past been some concern that oats can cause mucosal damage, but recent evidence suggests that pure and uncontaminated oats can be safely ingested by most patients with CD, provided they are eaten in limited quantities.
Signs and symptoms or laboratory abnormalities persisting despite six to 12 months on a GF diet occurs in about 7-30% of patients. This can be due to many distinct aetiologies, including inadvertent gluten ingestion (the most common cause), other food intolerances (including lactose and fructose intolerance), small intestinal bacterial overgrowth, microscopic colitis, pancreatic insufficiency, irritable bowel syndrome and refractory CD (RCD).
RCD is defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy, despite a strict GF diet for more than 12 months and in the absence of other disorders, including lymphoma.
RCD is rare, affecting 1-2% of patients with CD. There are two types of RCD, type I and type II.
Management of RCD includes the exclusion of unintentional gluten exposure and the treatment of any nutritional deficiencies.22-25
Recent reports have suggested that budesonide or small intestinal release mesalamine may be effective, with fewer side-effects, in type 1 RCD.26-28 Parenteral nutrition may be required in type II RCD, as symptoms are severe and usually do not respond to therapy.
Future potential treatments for patients with RCD include the development of genetically detoxified grains, oral and intranasal 'coeliac vaccines' to induce tolerance, inhibitors of TTG, and detoxification of immunogenic gliadin peptides via oral peptidase supplement therapy.29
Section 4: Prognosis
Studies carried out before the widespread introduction of GF diets reported mortality in patients with CD of up to 20%, due to malnutrition. However, it is now recognised that CD has a more benign course.
Factors that increase mortality in the condition are delayed diagnosis, severe symptoms and the first three years after diagnosis.30-32
Most deaths are attributed to T cell non-Hodgkin's lymphoma.
A reduced risk of breast cancer, lung cancer33and possibly vascular disease34 has been noted.
Long-term follow-up is essential in patients with CD because of the risk of complications and increased mortality. There is also evidence that suggests routine follow-up increases adherence.35,36
The follow-up care of patients with CD varies substantially across the UK, ranging from attendance at specialist clinics to simply being discharged back into the community.
A recent patient survey suggested that patients prefer follow-up with a dietitian, but with access to a gastroenterologist if required.37,38
British Society of Gastroenterology guidelines suggest that patients have FBC, bone profile, ferritin, folate and vitamin B12 levels checked every year. Bone densitometry should be monitored. It is also important to review dietary adherence.
Clinicians should be aware of possible complications, including lymphoma, and investigate or refer if there are clinical suspicions.
Section 5: Case study
A 52-year-old white woman presented with decreased appetite, abdominal pain, bloating and diarrhoea for more than a year.
She had been treated for irritable bowel syndrome by her GP, with no response. She also reported weight loss. Her symptoms varied with diet and she always felt lethargic. She was otherwise well and not on regular medication. She was a non-smoker and teetotal.
Her cousin had coeliac disease, but other family members were well.
The patient weighed 50kg. Apart from mild ankle oedema, physical examination was unremarkable.
Laboratory investigations revealed iron deficiency anaemia (Hb 10.5mg/dL, MCV 72fL, ferritin 10 microgram/L) and mild hypoalbuminaemia. TTG was weakly positive. Upper GI endoscopy and duodenal biopsy were carried out.
Histopathology revealed increased intraepithelial cells and partial villous atrophy.
The patient's genotype testing showed HLA-DQ2.
The clinical features and laboratory investigations were consistent with a diagnosis of coeliac disease, so she was managed with a GF diet and followed up regularly by the specialist dietitian and in the gastroenterology clinic.
She responded well on the GF diet and gained weight. Repeat investigations showed normalisation of TTG and resolution of the anaemia. Endoscopy and duodenal biopsy after one year showed normal appearances. She will have annual follow-up with the specialist team.
Section 6: Evidence base
- Phase I study of humanized Mik-beta-1 monoclonal antibody. Mayo Clinic, US, March 2013.
This continuing study is assessing the use of a monoclonal antibody (HU-Mik-beta-1) in the treatment of patients with refractory CD.
- Phase 2a, randomized, double-blind, placebo-controlled parallel-group study to evaluate the efficacy and safety of AMG 714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge. US and Finland, April 2015.
- NICE. Coeliac disease. Recognition, assessment and management. NG20. London, NICE, Sept 2015.
- Ciclitira PJ, Dewar DH, McLaughlin SD et al. British Society of Gastroenterology. The management of adults with coeliac disease. www.bsg.org.uk/images/stories/clinical/bsg_ coeliac_10.pdf
- British Society of Gastroenterology. Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease. London, British Society of Gastroenterology, June 2007. www.bsg.org.uk/pdf_word_docs/ost_coe_ibd.pdf
- Coeliac UK (www.coeliac.org.uk) provides information and a nationwide support network.
Dr Arun Rajendran, ST5 gastroenterology, St Mary's Hospital, London, and Dr Jeremy Nightingale, consultant gastroenterologist, Leonard-Jones intestinal failure unit, St Mark's Hospital, Harrow, Middlesex.
This is an updated version of an article that was first published in March 2014
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