Synonyms: gluten-sensitive enteropathy, celiac disease, celiac sprue
This is an immune-mediated, inflammatory systemic disorder provoked by gluten and related prolamines in genetically susceptible individuals, which can lead to malabsorption of nutrients.[1, 2]Gluten is a protein found in wheat, rye and barley.
It is a multigenetic disorder, associated with HLA types HLA-DQ2 (90%) or HLA-DQ8, plus other genetic or environmental factors. HLA typing indicating lack of DQ2 or DQ8 has a high negative predictive value, which may be useful if trying to exclude coeliac disease.
There is a familial tendency (10-15% of first-degree relatives will also be affected) and identical twins' concordance is 70%. It is theoretically possible, by HLA testing, to provide more accurate information to parents with a child with coeliac disease (CD) about the real risk for another child having the disease, including an antenatal assessment.
One study found a four-fold increase in the incidence of CD in the UK between 1990 and 2011, with the highest incidence in those aged 50-69 years.
It may present at any age.[2, 3]CD can be difficult to recognise because of the wide variation in symptoms and signs. Many cases may be asymptomatic. There may be a very long delay from the onset of symptoms until the diagnosis is made.
The National Institute for Health and Care Excellence (NICE) recommends that serological testing for CD should be offered for people:
- Who have persistent unexplained abdominal or gastrointestinal symptoms.
- Who have faltering growth.
- With prolonged fatigue.
- With unexpected weight loss.
- With severe or persistent mouth ulcers.
- Who have unexplained iron, vitamin B12 or folate deficiency.
- With type 1 diabetes (at the time of diagnosis).
- With autoimmune thyroid disease (at the time of diagnosis).
- With Irritable bowel syndrome (IBS) - in adults.
- Who are first-degree relatives of people with coeliac disease.
NICE also recommends serological testing for coeliac disease in people with any of the following:
- Metabolic bone disorder (reduced bone mineral density or osteomalacia).
- Unexplained neurological symptoms (particularly peripheral neuropathy or ataxia).
- Unexplained subfertility or recurrent miscarriage.
- Persistently raised liver enzymes with unknown cause.
- Dental enamel defects.
- Down's syndrome.
- Turner syndrome.
Dermatitis herpetiformis (a chronic, polymorphic, pruritic skin disease) is the classic skin manifestation of CD.Almost all patients with the rash have either detectable villous atrophy (approximately 75%) or minor mucosal changes. Lamellar ichthyosis has also been reported in association with CD.
Neurological presentations in CD
CD is associated with neurological and psychiatric disorders including cerebellar ataxia, peripheral neuropathy, epilepsy, dementia and depression. It is also considered that a broader spectrum of neurological syndromes may be the initial presentation of gluten sensitivity with or without intestinal pathology. These include migraine, encephalopathy, chorea, brainstem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barré-like syndrome and neuropathy with positive antiganglioside antibodies.
However, studies of gluten-free diet in patients with gluten sensitivity and neurological syndromes have shown variable results and diet trials have been inconclusive in autism and schizophrenia, in which sensitivity to dietary gluten has been implicated.[10, 11]
Any test for CD is accurate only if a gluten-containing diet is eaten during the diagnostic process. The person should not start a gluten-free diet until diagnosis is confirmed by a specialist, even if the results of a serological test are positive. For people who have restricted their gluten intake or excluded gluten from their diet and are reluctant or unable to re-introduce gluten into their diet before testing, refer to a gastrointestinal specialist but explain that it may be difficult to confirm their diagnosis by intestinal biopsy. Serological testing for CD should not be offered in infants before gluten has been introduced into the diet.
Always have a low threshold for re-testing people if they develop any symptoms consistent with CD.
CD-specific antibodies include auto-antibodies against tissue transglutaminase type 2 (tTGA2), including endomysial antibodies (EMAs), and antibodies against deamidated forms of gliadin peptides (DGPs). These are measured in blood. NICE recommends:
- For suspected CD in young people and adults:
- Total immunoglobulin A (IgA) and IgA tissue transglutaminase (tTG) as the first choice.
- IgA EMAs if IgA tTG is weakly positive.
- Consider using IgG EMA, IgG DGP or IgG tTG if IgA is deficient.
- For suspected CD in children:
- Total IgA and IgA tTG as the first choice.
- Consider using IgG EMA, IgG DGP or IgG tTG if IgA is deficient.
- HLA DQ2 (DQ2.2 and DQ2.5)/DQ8 testing should only be used in the diagnosis of CD in specialist settings (eg, children who are not having a biopsy, or people who already have limited gluten ingestion and choose not to have a gluten challenge).
- FBC shows anaemia in 50%; iron and folate deficiency are both common (microcytes and macrocytes), hypersegmented leukocytes and Howell-Jolly bodies (splenic atrophy). Also check B12, folate, ferritin, LFTs, calcium and albumin.
- LFTs may show elevated transaminases which should return to normal on a GFD. If they don't, consider associated autoimmune disease, ie primary biliary cirrhosis, autoimmune hepatitis or primary sclerosing cholangitis.
- Small-bowel barium studies are occasionally needed to exclude other causes of malabsorption and diarrhoea and to diagnose rare complications such as obstruction or lymphoma.
A biopsy is still needed to diagnose CD.Patients will need to stay on gluten until after the biopsy. The biopsy is obtained by upper gastrointestinal endoscopy or by suction capsule.
- Histological examination of the mucosa classically shows 'subtotal villous atrophy' and results in malabsorption - however, mucosa is of normal thickness, the villous atrophy is compensated by crypt hyperplasia. There should be full clinical remission on excluding gluten from the diet.
- Under these circumstances, tTGA or EMAs found at the time of diagnosis and their disappearance after gluten exclusion, means that it is only necessary to perform a further biopsy (and even a further gluten challenge and more biopsies) if there are still doubts.
- Refer young people and adults with positive serological test results to a gastrointestinal specialist for endoscopic intestinal biopsy to confirm or exclude CD.
- Refer children with positive serological test results to a paediatric gastroenterologist or paediatrician with a specialist interest in gastroenterology for further investigation for CD.
- Refer people with negative serological test results to a gastrointestinal specialist for further assessment if CD is still clinically suspected.
Non-coeliac gluten sensitivity
This is an umbrella term and may incorporate a wide range of possible clinical features. Some people report gluten-related symptoms but without evidence of CD. There is evidence suggesting that, even in the absence of CD, gluten-based products can induce abdominal symptoms which may present as IBS. The spectrum of gluten-related disorders includes CD, wheat allergy and non-coeliac gluten sensitivity. In all three conditions symptoms improve on the withdrawal of gluten.
The true prevalence in the general population is unknown and there are currently no specific biomarkers to identify non-coeliac gluten sensitivity. The long-term outcome for these patients is also unknown.
Treatment with a lifelong strict gluten-free diet (GFD) is currently the only treatment of known effectiveness.
Starting a GFD rapidly induces clinical improvement, which is mirrored by the mucosa. The diet consists of no wheat, barley, rye, or any food containing them (eg, bread, cake, pies).Information regarding foods that can be prescribed for people with CD can be found in Appendix 2 (Borderline substances) of the British National Formulary (BNF) and the BNF for children.[14, 15]
Information and support
Explain to people who are thought to be at risk of CD that a delayed diagnosis, or undiagnosed CD, can result in continuing ill health and serious long-term complications.
Provide sources of information on the disease, including national and local specialist coeliac groups and dieticians with a specialist knowledge of CD.
A healthcare professional with a specialist knowledge of CD should explain the importance of a GFD and give them information to help them follow it. This should include:
- Information on which types of food contain gluten and suitable alternatives, including gluten-free substitutes.
- Explanations of food labelling. The Food Information Regulations (2014) state that all allergens (eg, wheat, rye, barley and oats) must be emphasised in the list of ingredients.
- Information sources about GFDs, recipe ideas and cookbooks.
- How to manage social situations, eating out and travelling away from home, including travel abroad.
- Avoiding cross-contamination in the home and minimising the risk of accidental gluten intake when eating out.
- The role of national and local coeliac support groups, including Coeliac UK.
Advice on dietary management
Explain to people with CD (and their family members or carers, where appropriate):
- That they should seek advice from a member of their healthcare team if they are thinking about taking over-the-counter vitamin or mineral supplements.
- That they may need to take specific supplements such as calcium or vitamin D if their dietary intake is insufficient.
- That they can choose to include gluten-free oats in their diet at any stage and they will be advised whether to continue eating gluten-free oats depending on their immunological, clinical or histological response.
- Consider referring people with CD for endoscopic intestinal biopsy if continued exposure to gluten has been excluded and:
- Serological titres are persistently high and show little or no change after 12 months; or
- They have persistent symptoms, including diarrhoea, abdominal pain, weight loss, fatigue or unexplained anaemia.
- Do not use serological testing alone to determine whether gluten has been excluded from the person's diet.
- Offer an annual review to people with CD. During the review:
- Measure weight and height.
- Review symptoms.
- Consider the need for assessment of diet and adherence to the GFD.
- Consider the need for specialist dietetic and nutritional advice.
- Consider the need for a dual-energy X-ray absorptiometry (DEXA) scan (in line with the NICE guideline on osteoporosis) or active treatment of bone disease.
- Also consider the need for specific blood tests, the risk of long-term complications and comorbidities and the need for specialist referral.
- Blood tests that may need to be considered include FBC, LFTs, calcium and albumin, B12, folate, serum ferritin. Low haemoglobin, red cell folate and serum ferritin may suggest persisting malabsorption warranting further assessment.
Non-responsive and refractory coeliac disease
For people with CD who have persistent symptoms despite advice to exclude gluten from their diet:
- Review the certainty of the original diagnosis.
- Refer the person to a specialist dietician to investigate continued exposure to gluten.
- Investigate potential complications or co-existing conditions which may be causing persistent symptoms, such as IBS, lactose intolerance, bacterial overgrowth, microscopic colitis or inflammatory colitis.
Diagnose refractory CD if the original diagnosis of CD has been confirmed and exposure to gluten and any co-existing conditions have been excluded as the cause of continuing symptoms.
Refer people with refractory CD to a specialist centre for further investigation. Consider prednisolone for the initial management of the symptoms of refractory CD in adults while waiting for specialist advice.
Delayed diagnosis of CD may result in continuing ill health, osteoporosis, miscarriage and a modest, increased risk of intestinal malignancy (in adults); also, growth failure, delayed puberty and dental problems (in children).
- Nutrient deficiencies - eg, vitamin D and iron.
- Cancer risk - there is conflicting research on this subject. Some research shows a small increase in overall risks of developing malignancy - eg, gastrointestinal cancers and some types of lymphoma.Intestinal lymphoma usually presents with the return of bowel symptoms, although it usually responds poorly to treatment.
- Ulcerative jejunitis.
- Functional hyposplenism: some degree of splenic atrophy is present in most patients with CD.
- People with CD may experience anxiety and depression.
- Untreated CD is associated with infertility in men and women but this resolves on a GFD.
- Poor fetal outcome in pregnant women with undiagnosed CD but not in diagnosed CD.
Patients often find it difficult to be fully compliant with a GFD, particularly adolescents.The long-term health risks for patients who comply poorly with a GFD include nutritional deficiency and reduced bone mineral density. Many coeliac patients have an inadequate energy intake. Poor absorption often leads to inadequate intake of calcium and vitamin B6 and vitamin D. About a quarter of patients with CD have osteoporosis of the lumbar spine compared with 5% of matched controls. Bone mineral density improves significantly with a GFD.
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