Celiac diseaseK90.0

Non-allergic, lifelong persistent, immunologically mediated, chronic, inflammatory multi-organ disease that manifests itself in people with genetically determined risk (HLA-DQ2 and HLA DQ8 expressions) (98% of all coeliac disease patients have these HLA antigens, but also around 30% of the population. Of these, only 3% develop the disease).

Coeliac disease is the result of a misdirected and therefore pathological immune response to gliadin (alcohol-soluble fraction of gluten, a gluten protein from cereals) and related proteins found in wheat, rye, barley and other cereals. The pathological immune reactions lead to inflammatory changes in the small intestine and potentially to a broad spectrum of systemic complications ("chameleon of gastroenterology").

The tissue transglutaminase 2

The intestinal damage can in turn lead to malabsorption of nutrients(iron deficiency, iron deficiency anemia, folic acid and vitamin B12 deficiency) and corresponding secondary diseases. In recent years, other wheat-induced diseases such as wheat allergy andnon-celiac gluten sensitivity(NGS) have been described.

Early detection of coeliac disease is of particular clinical relevance, as continued exposure to gluten in undiagnosed coeliacs can increase the risk of other autoimmune diseases (e.g. type 1 diabetes mellitus; autoimmune thyroiditis) (Cosnes J et al. 2008).

Classic celiacdisease: diarrhea, weight gain, malabsorption syndrome, failure to thrive in childhood

Symptomatic coeliac disease: like "classic coeliac disease" but without malabsorption syndrome; gastrointestinal symptoms may be completely absent

Extraintestinal symptoms: dermatitis herpetiformis; iron deficiency anemia (most common symptom in adults), tongue burning, atrophic reddened tongue, osteoporosis, chronic hepatitis, arthritis, etc.

Subclinical coeliac disease: Positive antibodies and pathological small intestine biopsy without symptoms of disease

Potential coeliac disease: Asymptomatic patients with positive anti-Tg2-IgA test and normal small intestine biopsy (incidental diagnosis, diagnosis as part of family investigations)

Refractory celiac disease (RDC): Celiac disease patients in whom a gluten-free diet does not result in clinical improvement within one year. A distinction is made between 2 types:

In type II, an enteropathy-associated T-cell lymphoma (EATL) can develop.

The frequency of the disease varies considerably in different countries. Prevalences of 1:500 are reported in Germany and Denmark, 1:110 in the USA and Great Britain, and a worldwide average of around 1:270. There is no good epidemiological data on the frequency of other wheat-dependent diseases. Experts assume that between 0.5 and 7% of the population are affected. According to self-assessment by adults, up to 13% of the population is affected (Kratzer W et al. 2013). Increase in incidence in recent years. The increase points to environmental factors (e.g. gastrointestinal infections, changes in dietary habits, psychosocial factors) as risk factors for the development of coeliac disease and the autoimmune diseases associated with it.

Some diseases occur more frequently with coeliac disease (see below). Clinic)

Gender distribution: 70 % of patients are female.

Gliadins and glutenins lead to a complex reaction of the intestinal mucosa and the immune system in zoeliac disease. Enterocytes of the small intestine produce an increased number of different HLA classes (especially HLA DQ2, HLADQ8). 98% of coeliac disease patients have these HLA antibodies, but also 30% of the normal population. Certain sections of the gluten protein (gliadin peptides) bind to the increased HLA DQ2 antigens. It is noteworthy that gluten components only trigger the immune reaction when they have been modified by transglutaminase 2 (TG2). Inhibition of TG2 may offer a therapeutic approach.

To date, around 40 CD-active peptides (short amino acid sequences - epitopes - recognized by the immune system) have been identified in wheat gluten proteins and related proteins from barley and rye (Sollid LM et al. 2020). However, a number of other proteins, including ATIs, have been identified that may play a potentiating role in CD (Junker Y et al. 2012; Zevallos VF et al. 2017). Although gluten proteins are the main triggers of CD, the role of other proteins and triggers (such as viral infections) is less clear and requires further research (Geisslitz S et al. 2022).

People with an increased risk of coeliac disease are in particular first-degree relatives of a person with coeliac disease (risk 10-15%), people with type 1 diabetes mellitus (risk up to 9%) and autoimmune thyroiditis (risk up to 10%) and trisomy 21. Second-degree and higher relatives also have a slightly increased risk of coeliac disease. If there are corresponding symptoms, the indication for a diagnosis should be made generously.

Various antibodies are formed. In addition to antibodies against the gluten protein itself (gliadin antibodies), antibodies against tissue transglutaminase also occur. Tissue transglutaminase 2 (TG2) is the autoantigen of the anti-endomysial antibody (EMA).

The inflammatory process leads to apoptosis of the enterocytes and atrophy of the villi. This results in a reduction of the resorption surface and resorption disorders.

There are 2 manifestation peaks.

Only a few children develop coeliac disease before the age of 6 months. The first symptoms usually appear 3-6 months after the start of the gluten-containing diet, e.g. with semolina porridge, wholemeal porridge, etc.

A second peak of manifestation occurs in the 4th decade of life.

Classic coeliac disease

• This includes both patients with a "classic" enteric form of the disease and those with "atypical symptoms", e.g. extraintestinal symptoms. Symptoms usually begin between the ages of 1 and 3. Classic coeliac disease as gluten-induced enteropathy manifests itself with signs of malabsorption such as weight loss, steatorrhea and protein deficiency oedema. When the clinical picture is fully developed, a distended abdomen, voluminous foul-smelling dyspeptic diarrhea, muscle hypotrophy, anorexia and changes in temperament (e.g. tearfulness) can already be seen in infants. Iron deficiency or growth retardation are also typical signs in childhood. However, the appearance of "classic" coeliac disease has changed to such an extent that the classic form of infancy is no longer the most common manifestation (Newnham ED 2017). Most people with symptomatic coeliac disease are adults. They suffer from abdominal complaints such as dyspepsia, flatulence or changes in bowel habits. Insomnia, fatigue, depression or constipation can also be symptoms. It is not uncommon for laboratory chemical changes, e.g. a (slight) increase in transaminases or thyroid dysfunction, to be the only indicators. The number of people diagnosed due to gastrointestinal symptoms is decreasing. The number of cases detected during screening (laboratory screening) of at-risk groups is increasing (Reilly N R et al. 2011).

Symptomatic coeliac disease

• The term "symptomatic or atypical celiac disease" is used to describe constellations such as elevated transaminases, neurological-psychiatric changes (e.g. migraine, epilepsy, depression), iron deficiency anemia as the most common symptom in adults, glossodynia, atrophic red tongue, osteoporosis, chronic hepatitis, arthritis. Furthermore, "dermatitis herpetiformis Duhring" is a well-described clinical picture. Malabsorption syndromes are absent. In 40% of cases any gastrointestinal symptoms are absent (Corazza G R et al. 1993; Bottaro G et al. 1999; Meloni G et al. 1999).

Subclinical coeliac disease (silent coeliac disease)

• Patients with "asymptomatic celiac disease" have a celiac disease-specific serology (including HLA DQ2/8 detection) and typical changes in the small intestine biopsies (at least MARSH 2). They show no abnormalities even after careful history taking and physical examination as well as orienting laboratory diagnostics. Following the introduction of a gluten-free diet (GFD), no positive changes are usually observed. The now uncommon term "silent coeliac disease" was also used for this situation. People with asymptomatic coeliac disease are usually identified as part of population-based screening programs, when testing first-degree relatives or in a targeted search for possible causes of comorbidities. A reduced quality of life or other minor symptoms such as extraintestinal manifestations (e.g. fatigue syndrome) can be signs of subclinical coeliac disease.

Refractory coeliac disease

• Refractory coeliac disease (in approx. 1-2% of all people with coeliac disease) is present if intestinal or extraintestinal symptoms persist or recur despite a strict gluten-free diet for 12 months and evidence of new or persistent villous atrophy. The classification of refractory coeliac disease into type I and type II is based on the characterization of the infiltrating T cells, for which additional immunohistological and molecular analyses must be used. While in type I refractory celiac disease there is generally no T-cell clonality and the same surface antigens (CD3/CD8) are detected as in uncomplicated celiac disease, in type II refractory celiac disease PCR-based T-cell receptor analysis reveals T-cell clonality and immunohistological evidence of a loss of surface antigens (CD3/CD8) in more than 50% of the intraepithelial T cells. Immunohistology and molecular pathology complement each other in their informative value. T cell clonality and aberrant immunophenotype indicate a neoplastic transformation of the T lymphocytes, but are not specific for refractory celiac disease on their own and can also be observed - usually transiently - in uncomplicated celiac disease with gluten exposure. The combination of positive clonality findings and aberrant antigen expression, on the other hand, has a high specificity and high predictive value with regard to the development of enteropathy-associated lymphoma (de Mascarel A et al. 2008) It can be assumed that an EATL develops from an aberrant T-cell clone in refractory celiac disease type II.

Latent celiac disease

• Latent coeliac disease is defined as a constellation with positive coeliac disease-specific serology and currently normal small intestinal mucosa on a normal diet, but evidence of pathological small intestinal histology in the past. Other authors understand this to mean undiagnosed coeliac disease or a potential for coeliac disease in people with other autoimmune diseases. Overall, the term does not appear to be appropriate.

Potential coeliac disease

• The term "potential coeliac disease" applies to people who have a positive, coeliac-specific antibody constellation in their serum. Histological assessment of the small intestinal mucosa does not reveal any pathological findings. Other definitions for this patient group refer to individuals who have a positive serology and in whom an increased number of intraepithelial lymphocytes (MARSH 1) can be detected in the duodenum (this finding corresponds to a histological constellation with low specificity). According to a recent study, about 20% of all persons with celiac disease-specific serology showed no changes in the duodenum. Potential coeliac disease would therefore be a relatively common clinical constellation (Biagi F et al. 2013).

Clinical symptoms:

• Motility disorders, from diarrhea to constipation
• Nausea and vomiting
• Flatulence
• Chronic abdominal pain
• Bloated abdomen
• Weight loss
• Growth disturbance in the child
• Anemia (often iron deficiency anemia)
• Osteomalacia/osteoporosis
• Changes in tooth enamel
• Peripheral neuropathy/polyneuropathy
• Tetany/muscle weakness
• Night blindness
• Hematomas
• oedema
• Recurrent oral aphthae (especially in children)

Comorbidities:

Autoimmune diseases (Lundin KE et al. 2015)

• Type 1 diabetes mellitus (the prevalence of celiac disease in pediatric and adult type 1 diabetics is reported at 4.4% to 11%.
• Hashimoto's thyroiditis
• Autoimmune hepatitis
• PBC(primary biliary cirrhosis)
• Collagenoses(Sjögren's syndrome/ systemic lupus erythematosus)
• Addison's syndrome
• IgA deficiency: IgA deficiency is significantly more common in people with coeliac disease than in the normal population (about 5%).
• Irritable bowel syndrome (IBS ): For those affected, there is an overall approximately 4-fold increased risk of coeliac disease. Screening IBS patients for coeliac disease makes sense. In people with microscopic colitis, concomitant coeliac disease is detected in approx. 5% of cases
• Lactose intolerance (caused by a secondary lactase deficiency - pathological H2 breath test after administration of lactose)

Neurological-psychiatric diseases:

• Migraine: a prevalence study describes a 3.8-fold increased risk of migraine for people with coeliac disease.
• Epilepsy: A large epidemiological study (n= 29,000 celiac disease patients and 143,000 controls) describes an up to 1.7-fold increased risk for the manifestation of epilepsy.
• Depression and anxiety disorders

Skin diseases (see celiac disease skin changes below)

• Dermatitis herpetiformis Duhring (DhD is an epiphenomenon of gluten-sensitive enteropathy)
• Psoriasis: The risk of developing psoriasis is increased by a factor of 1.7 (1.54-1.92) in people with coeliac disease.
• Pyoderma

Genetic syndromes

• Down syndrome/trisomy(6%)
• Turner syndrome/monosomy X (8%)

Other diseases or symptoms or symptom complexes

• Bronchial asthma
• Transaminase elevations
• Osteopathy (osteomalacia, osteoporosis)
• Microscopic colitis
• Lymphoproliferative diseases (enteropathy-associated T-cell lymphoma)
• Sarcoidosis (Skroza N et al. 2014)

Very sensitive serological antibody tests not only enable the diagnosis of coeliac disease, but are also suitable for monitoring the course of the disease. The following antibody tests are available:

• Antibodies against tissue transglutaminase IgG/IgA
• Antibodies against endomysium IgG/IgA
• Antibodies against deamidated gliadin IgG/IgA

Antibodies against tissue transglutaminase IgG/IgA: Endomysium and transglutaminase IgA-Ak are very specific markers for the presence of celiac disease, and with the combination of these serological detections a high sensitivity and specificity in the diagnosis of celiac disease can be achieved.

Important: Up to 5% of coeliac disease patients suffer from an IgA deficiency. In these cases, IgA-Ak determinations are false negative and not useful. However, the IgG anti-transglutaminase 2 antibody remains positive. The total IgA should therefore always be determined in parallel. If IgA deficiency is known, the IgG-Ak should be determined.

Additional testing for IgG-Ak against deamidated gliadin maximizes the diagnostic sensitivity.

Important: Diagnosis should be made on a gluten-containing diet: the antibody titres drop on a gluten-free diet. However, the HLA markers remain positive. It is therefore necessary that the initial diagnosis is made on a gluten-containing diet. During the course of treatment, however, an annual check-up is recommended to monitor the gluten-free diet.

Exclusion of coeliac disease by means of HLA determination: The HLA characteristics DQ2 and DQ8 are a mandatory requirement for coeliac disease, 100% of coeliac disease patients carry one of these characteristics. The diagnosis of coeliac disease is ruled out in patients who do not carry these HLA characteristics. The HLA determination is not influenced by dietary measures.

Characteristic histological changes of celiac disease are:

• partial or total villous atrophy
• crypt hyperplasia
• changes in the ratio of villi to crypts
• increased mitoses in the crypts
• increased intraepithelial lymphocytes (IEL)
• increased mitoses in the intraepithelial lymphocytes and
• an increased infiltrate of plasma cells, lymphocytes, eosinophils and basophilic granulocytes in the lamina propria.

Marsh criteria in the histologic evaluation of small bowel or duodenal biopsies:

• Marsh0: <25IEL/100 enterocytes without crypt hyperplasia without villous atrophy
• Marsh1: >25IEL/100 enterocytes without crypt hyperplasia without villous atrophy
• Marsh2: >25IEL/100 enterocytes with crypt hyperplasia without villous atrophy
• Marsh3:
  • Marsh3a: >25IEL/100 enterocytes with crypt hyperplasia, mild to moderate villous atrophy
  • Marsh3b: >25IEL/100 enterocytes with crypt hyperplasia, subtotal villous atrophy
  • Marsh3c) >40IEL/100 enterocytes with crypt hyperplasia and total villous atrophy
• IEL = intraepithelial lymphocytes.

Medical history, clinical symptoms, biopsy of small intestine (clear histology); serology (IIF): IgA-AK against endomysium. Gliadin-AK (IgA- and IgG-AK in the first 2 years of life). Detection of IgA-AK against tissue transglutaminase (high specificity and sensitivity). 10 % of patients have an IgA deficiency at the same time (risk of a false negative finding of an IgA-mediated antibody constellation). Histological findings: Esophago-gastro-duodenoscopy with collection of duodenal mucosal biopsies is an essential part of the primary diagnosis of celiac disease in children, adolescents and adults.

Effect of a gluten-free diet: If people have already started a gluten-free diet without prior diagnosis (gluten-free > 2 months), antibodies are often no longer detectable!

Gluten stress test: To confirm the diagnosis, a gluten stress test should be performed in these cases. It is important to remember that the immunological reaction to gluten can vary greatly from person to person in gluten-sensitive individuals. In individual cases, smallest gluten quantities between 10mg and 50mg can trigger a relapse. In most cases, 3 g/day of gluten are sufficient to generate positive tTG-IgA antibodies after 4 weeks. A diagnostic gluten load may also be indicated in persons who have been diagnosed with celiac disease in the past and who have doubts about this diagnosis.

In the absence of symptoms (subclinical celiac disease), the certainty of the diagnosis depends on the clarity of the serology (antibody titre >3 times above the upper limit) and histology (Marsh 3). There may be subclinical celiac disease in which an improvement in general condition is only noticed after the onset of GFD.

Laboratory diagnostics: In the initial diagnosis, it is recommended to determine the following additional laboratory values: blood count, vitamin B12, folic acid, ferritin, transaminases, calcium, fasting glucose, vitamin D level (25-OH-chollecalciferol), alkaline phosphatase, zinc, thyroid-stimulating hormone (TSH). Other autoantibodies should only be determined in case of clinical suspicion.

Wheat allergy (mostly IgE-mediated immunological reaction against wheat proteins). In contrast to coeliac disease, wheat allergy usually involves IgE-mediated (more rarely T-cell-mediated) reactions against various wheat proteins, including omega 5 gliadin, gamma gliadin, amylase trypsin inhibitors (ATIs), thioredoxin or lipid transfer proteins (Inomata N 2009).

Non-celiac non-wheat allergy wheat sensitivity (non-celiac gluten sensitivity/NGS): wheat-dependent clinic, usually negative serology for celiac-specific antibodies), normal small intestine histology, usually negative specific IgE (wheat) and negative prick test (wheat); no malabsorption syndrome.

Drug-induced toxic villous atrophy (olmesartan, MTX)

As an autoimmune disease, celiac disease is associated with other diseases such as diabetes mellitus type 1 (about 5-10% of patients), IgA deficiency, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, autoimmune hepatitis, and dermatitis herpetiformis Duhring.

Secondary lactase deficiency (pathological H2 breath test after administration of lactose). Late complication is enteropathy-associated T-cell lymphoma (EATCL). Rare is the simultaneous occurrence of colitis in severe celiac disease. Late complication: Enteropathy-associated T-cell lymphoma (EATL).

Diet: Lifelong gluten-free diet (see Table 1), i.e. cereal content < 50 mg/100 g cereal products (dry weight), limit 10 mg/100 g.

If necessary, iron, Vit. _B12, folic acid and Vit. D substitution.

• Iron supplementation: Hb deficit in g/l times 25 = total iron requirement in mg.
  • Orally: (Ferro sanol duodenal) 2(-3)times/day 50 mg, later 2(-3)times/day 100 mg p.o., if possible on an empty stomach. Infants 5 mg/kg bw/day p.o., divided into 3 doses over 3 months.
  • Rarely intravenously (e.g. Ferrlecit): Adults 3.2-5.0 ml/day slowly i.v.
  • Control: Reticulocytes, Hb increase only later. Continue to give until 3 months after normalization of blood count. Caution! No simultaneous administration with tetracyclines, antacids, colestyramine, penicillamine.
  • Side effects include nausea, constipation, diarrhea and black discoloration of the stool.
• Vit. B12 _substitution(Neurotrat B12): Induction with 1000-2000 μg/week i.m., i.v., or s.c. Reticulocytes increase after 5-8 days. Maintenance dose: 100-300 μg/every 2 months.
• Folic acid substitution (Folic acid Hevert): Adults: 5-15 mg/day p.o. Children: 5-10 mg/day p.o. over 4 weeks or 0.2 mg/day parenterally over 4 weeks.
• Vit. D substitution: Vit _D3 (e.g. Dekristol, Vigantoletten) 5000-10,000 IU/day p.o. for 6 weeks, later 2000-50,000 IU/day for several months. Calcium intake is essential: 1 g calcium/day (250 mg p.o. 4 times/day).

Alternatively: oral endopeptidases, gluten-binding polymers, tTG inhibitors (ZED 1227 in clinical trials), HLA-DQ blocking peptides or various biologics (e.g. anti-IL-15 or zonulin-blocking peptide).

Experimental: vaccination with immunoreactive gliadin peptides (currently being tested in initial clinical trials).

In children and adolescents during growth, substitution with Vit D3 400 IU/day p.o. or UV radiation.

Allowed foods:

• Potatoes, rice, corn, amaranth, millet, all types of starch, including wheat starch, buckwheat, quinoa, soybeans, teff (type of millet), chestnut, plantain.

Foods not permitted:

• Wheat, oats, barley, rye, spelt, kanut, emmer, einkorn, green spelt, as well as all baked goods/pasta, breads, flours or flakes made from these grains.
• Hidden gluten in sauces, soups, breakfast drinks, sweets, chewing gum and ready-made products such as cake mixes.

Note: According to an EU directive, gluten has had to be labeled on finished products since 2004 and also on counter sales since 2014. Today, many food markets offer a variety of gluten-free products. This makes it easier to find and stick to the diet.

Professional nutritional advice and training is helpful.

Older terms such as "overte" "silente", "latent", "atypical", "asymptomatic" or "oligosymptomatic" celiac disease are no longer used in the new literature.

The average adult diet contains 10-20 g gluten/day (up to 40 g/day in some countries). The gluten content of a slice of wheat bread is about 6-7% of the total weight. 6 slices of bread contain about 15 grams of gluten. This value may vary depending on the thickness of the slice.

Further information: German Celiac Disease Society.

For further information please contact:

• German Coeliac Society
• Association of Europeam Coeliac Societies (AOECS)

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