Zöliakie

Synonyms: gluten-sensitive enteropathy, celiac disease, celiac sprue

Hintergrund

Coeliac disease, also known as gluten-sensitive enteropathy, is an autoimmune inflammatory systemic disorder provoked by an immune-mediated response to dietary gluten, a protein found in wheat, rye and barley. It is characterized by small bowel enteropathy (villous atrophy, intra-epithelial lymphocytosis, and crypt hyperplasia), a wide range of gastrointestinal and/or systemic symptoms, and the presence of coeliac-specific autoantibodies.

Ätiologie

The aetiology of coeliac disease is multifactorial, involving a combination of genetic, environmental, and immunological factors. HLA types HLA-DQ2 (90%) or HLA-DQ8 are found in most patients with coeliac disease; however many people with these genes do not develop coeliac disease, suggesting that other environmental or immunological factors are needed to trigger the development of the condition. HLA typing indicating lack of DQ2 or DQ8 has a high negative predictive value, which can be useful if trying to exclude coeliac disease.

Environmental risk factors for coeliac disease include:¹

• Being small for gestational age.

• Elective (but not emergency) caesarean delivery.

• Infection with rotavirus or campylobacter. (Rotavirus vaccination may be protective).

• Lack of helicobacter pylori colonisation.

• Use of proton pump inhibitors.

• Use of antibiotics.

• Higher maternal educational achievement.

• Maternal non-smoking status.

Epidemiologie²

Coeliac disease has historically been reported to affect 1% of the global population. The prevalence is the same in the UK; however, only 10-20% will have been diagnosed as having coeliac disease. Coeliac disease affects all ethnic groups but there are higher rates in those of European descent, people from Saudi Arabia and people from the Saharawi (an ethnic group from the Western Sahara). Women are diagnosed more frequently than men.

There is evidence that the incidence of coeliac disease has increased over the past 50 years with some estimates of current prevalence being as high as over 3%.¹

Coeliac disease is more common in those with other autoimmune conditions. It occurs in up to 16.4% of those with type 1 diabetes.

There is a familial tendency; 7.5% of first degree relatives will be affected with 8.9% of siblings, 7.9% of offspring, 3% of parents and 70% of identical twins also having the disease.

Coeliac disease can develop at any age, including in the elderly. This may be as a result of longstanding previously undiagnosed coeliac disease, but it is also may result from new loss of gluten tolerance. However, recent studies suggest that the majority of people with coeliac disease develop it before the age of 10 years.¹

Präsentation

Coeliac disease 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 coeliac disease symptoms until the diagnosis is made.

Symptoms can be divided into gastro-intestinal and extra-intestinal and also separately into those most typically experienced by adults and children. There are few pathognomonic symptoms but this is a list of the most commonly reported.

Gastrointestinal symptoms:

Erwachsene:

• Durchfall.

• Unerklärlicher Gewichtsverlust.

• Blähungen.

• Abdominale Distension.

• Bauchbeschwerden.

• Übelkeit.

• Erbrechen.

• Steatorrhea.

• Verstopfung.

Children:

• Schlechte Gewichtszunahme.

• Decreased appetite.

• Reizbarkeit.

• Durchfall.

• Abdominale Distension.

• Erbrechen.

• Verstopfung.

Extra-intestinal symptoms

These are mostly the result of nutritional deficits due to the malabsorption caused by the enteropathy.

Erwachsene:

• Dermatitis herpetiformis. This intensely itchy vesicular rash is pathognomonic for coeliac disease. Almost all patients with the rash have either detectable villous atrophy (approximately 75%) or minor mucosal changes.

• Symptoms of anaemia: fatigue, pallor, breathlessness.

• Muskelschwäche.

• Chronic headaches.

• Ataxie.

• Parästhesien.

• Arthralgia.

• Muskelschmerzen.

• Knochenschmerzen.

• Osteopenia or osteoporosis with associated fractures.

• Unfruchtbarkeit.

• Recurrent pregnancy loss.

Children:

• Dermatitis herpetiformis. This intensely itchy vesicular rash is pathognomonic for coeliac disease. Almost all patients with the rash have either detectable villous atrophy (approximately 75%) or minor mucosal changes.

• Symptoms of anaemia: fatigue, pallor, breathlessness.

• Symptoms of ADHD (though this remains controversial).

• Arthralgia.

• Muskelschmerzen.

• Knochenschmerzen.

• Kleinwuchs.

• Dental enamel defects.

• Verzögerte Pubertät.

NICE Guidance³

The National Institute for Health and Care Excellence (NICE) recommends that serological testing for coeliac disease 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-Syndrom.

• Turner-Syndrom.

Lamellar ichthyosis has also been reported in association with CD.⁴

Neurological symptoms in coeliac disease⁵

Coeliac disease is associated with neurological and psychiatric disorders. Cerebellar ataxia is the most common of these; peripheral neuropathy, epilepsy, headaches and mild cognitive impairment ("brain fog") have also been described alongside depression, bipolar disorder, excessive anxiety, irritability, schizophrenia, attention-deficit/hyperactivity disorder, autism, and sleep complaints dementia and depression.

The pathophysiology of these associations remains controversial but includes gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and vitamin or nutrient deficiency. Also anti-neuronal antibodies may be an additional aetiological factor for neurological involvement in CD. One study detected the presence of anti-neuronal antibodies in 61% of patients with coeliac disease and neurological symptoms; in more than 50% of patients, the antibodies disappeared after one year of adherence to a gluten-free diet, accompanied by improvement/disappearance of neurological symptoms.

Untersuchungen⁶

Always have a low threshold for re-testing people if they develop any coeliac disease symptoms.

Specific auto-antibodies

Coeliac disease-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:⁶

• For suspected coeliac disease 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 coeliac disease 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 coeliac disease 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).

Weitere Untersuchungen

• FBC shows anaemia in 50%; iron and folate deficiency are both common (microcytes and macrocytes), hypersegmented leukocytes and Howell-Jolly bodies (splenic atrophy). B12, folate, ferritin, LFTs, calcium and albumin should also be tested.

• LFTs may show elevated transaminases which should return to normal on a gluten-free diet (GFD). If they don't, associated autoimmune disease, for example, primary biliary cirrhosis, autoimmune hepatitis or primary sclerosing cholangitis should be considered.

• 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.

Biopsy confirmation

The established diagnostic process for coeliac disease has been a two-step process, involving both a blood test to look for antibodies, and endoscopic biopsy to assess damage to the intestine. However, the British Society of Gastroenterology (BSG) issued interim new guidance for the diagnosis of coeliac disease, supported by Coeliac Disease UK, during the covid pandemic, prompted by the pause in non-urgent endoscopies. The new recommendations are that for many adults, the diagnosis can be made on the basis of blood tests alone. The guidelines were due to be updated again in 2025 but, at the time of writing, no update was available.⁷ International guidance still recommends biopsy diagnosis in adults.⁸

Not every patient will be suitable for the no-biopsy approach. In order to meet the criteria, the patient needs to be under 55 years of age with symptoms of coeliac disease, and who:

• Does not need an endoscopy to rule out other conditions.

• Has antibody levels (IgA tissue transglutaminase) at least 10 times the upper limit of normal.

• Has a second positive antibody blood test (endomysial antibodies (EMA) or tissue transglutaminase if EMA isn't available).

Guidelines have recommended a no-biopsy diagnosis for most children since 2013.⁹

The initial blood test can be done by a GP but the decision as to whether endoscopy with biopsy is needed and the final diagnosis of coeliac disease still need to be made by a gastroenterologist.

Patients still requiring a biopsy need to stay on gluten until it has been performed - this needs to be at least 6 weeks of 3 meals a day containing gluten. 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.

Überweisung⁶

• Refer young people and adults with positive serological test results to a gastrointestinal specialist for endoscopic intestinal biopsy to confirm or exclude coeliac disease.

• Refer children with positive serological test results to a paediatric gastroenterologist or paediatrician with a specialist interest in gastroenterology for further investigation for coeliac disease.

• Refer people with negative serological test results to a gastrointestinal specialist for further assessment if coeliac disease is still clinically suspected.

Differentialdiagnose

RDS, lactose or other Nahrungsmittelunverträglichkeiten, colitis (including inflammatory bowel disease), and other causes of Malabsorption.

Non-coeliac gluten sensitivity¹⁰

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 coeliac disease. There is evidence suggesting that, even in the absence of coeliac disease, gluten-based products can induce abdominal symptoms which may present as IBS. The spectrum of gluten-related disorders includes coeliac disease, 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.

Behandlung

Treatment with a lifelong strict gluten-free diet is the only coeliac disease treatment of known effectiveness. A low-gluten diet is ineffective; it is important that all gluten, including traces and cross-contamination, is avoided completely.

Starting a gluten-free diet rapidly induces clinical improvement, which is mirrored by the mucosa. The diet consists of no wheat, barley, rye, or any food containing them. Information regarding foods that can be prescribed for people with coeliac disease can be found in Appendix 2 (Borderline substances) of the British National Formulary (BNF) and the BNF for children.^{11 12}

Information and support⁶

Explain to people who are thought to be at risk of developing coeliac disease that a delayed diagnosis, or undiagnosed coeliac disease, 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 coeliac disease.

A dietician should explain the importance of a gluten free diet 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 gluten free foods, 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.

• Food labelling in the UK and the EU is clear with all allergens being labelled in bold. Some foods are specifically labelled "Gluten Free" but any foods not containing (or which do not state "may contain") wheat, barley, rye or oats are safe for people with coeliac disease. Some foods contain wheat starch from which the gluten has been removed. These are safe for people with coeliac disease to eat although a proportion of people with coeliac disease will also have a separate wheat intolerance.

Explain to people with coeliac disease (and their family members or carers, where appropriate):

• 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.

Überwachung⁶

• Consider referring people with coeliac disease 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.

• 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 gluten free diet.

  • Consider the need for specialist dietetic and nutritional advice.

• Consider the need for a dual-energy X-ray absorptiometry (DXA) scan (in line with the NICE guideline on osteoporosis) or active treatment of bone disease.¹³

• 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 disease⁶

For people with coeliac disease who have persistent symptoms despite advice to exclude gluten from their diet, most will be due to ongoing gluten intake. However it is important to:

• 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.

• Refer people with apparent refractory CD to a specialist centre for further investigation.

Komplikationen⁶

Delayed diagnosis of CD may result in continuing ill health, osteoporosis, miscarriage, and a modest increased risk of intestinal malignancy (in adults), as well as growth failure, delayed puberty, and dental problems (in children).

• Nutrient deficiencies - for example, vitamin D and iron.

• Osteoporose.

• Cancer risk - there is a 3-times higher risk of lymphoma than the general population.¹⁴ 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 coeliac disease. They are eligible for flu vaccines and other vaccines reserved for those with immunosuppression.

• Untreated coeliac disease is associated with infertility in men and women but this resolves on a gluten-free diet.

• Poor foetal outcome in pregnant women with undiagnosed coeliac disease but not in diagnosed coeliac disease.⁷

It has historically been difficult for people to maintain a fully gluten-free diet, avoiding all cross-contamination. There are more gluten-free foods available than ever before and many restaurants are aware of the needs of someone with coeliac disease. The long-term health risks for patients who comply poorly with a gluten free diet 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 coeliac disease have osteoporosis of the lumbar spine compared with 5% of matched controls. Bone mineral density improves significantly with a gluten free diet.