Celiac disease K90.0

Lifelong persistent, immunologically mediated, chronic inflammatory bowel disease that manifests in individuals with genetically determined risk (HLA-DQ2 and HLA DQ8 expressions). Celiac disease results from a misdirected and thus pathological immune response to gliadin (the alcohol-soluble fraction of gluten, a gluten protein found in grains), and related proteins found in wheat, rye, barley, and other grains. The pathological immune responses lead to inflammatory changes in the small intestine and potentially a wide range of systemic complications ("chameleon of gastroenterology").

Intestinal damage, in turn, can lead to malabsorption of nutrients(iron deficiency, iron deficiency anemia, folic acid and vitamin B12 deficiency) and corresponding sequelae. In recent years, other wheat-dependent diseases, such as wheat allergy and "non-celiacgluten sensitivity" have been described.

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

• Classic celiac disease: diarrhea, weight gain, malabsorption syndrome, failure to thrive in childhood.
• Symptomatic celiac disease: like "classic celiac disease" but without malabsorption syndrome; gastrointestinal symptoms may be completely absent
  • Extraintestinal symptoms: dermatitis herpetiformis; iron deficiency anemia (most common symptom in adults), burning tongue, atrophic red tongue, osteoporosis, chronic hepatitis, arthritis, and others.
• Subclinical celiac disease: Positive antibodies and pathological small intestine biopsy without symptoms of disease.
• Potential celiac disease: Asymptomatic patients with positive anti-Tg2 IgA test and normal small bowel biopsy (Incidental diagnosis, diagnosis during family screening).
• Refractory celiac disease (RDC): Celiac patients in whom a gluten-free diet does not produce clinical improvement within one year. 2 types are distinguished:
  • Enteropathy-associated T-cell lymphoma (EATL) may develop in type II.

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

Gender distribution: 70% of patients are female.

Gluten leads to a complex reaction of the intestinal mucosa and the immune system in zoeliac disease. Enterocytes of the small intestine produce increased numbers of different HLA classes (especially HLA DQ2, HLADQ8). 98% of celiac patients show these HLA antibodies, but also 30% of the normal population. Certain sections of gluten (gliadin peptides) bind to the increased HLA DQ2 antigens. It is noteworthy that gluten components do not fuel the immune response until they have been modified by transglutaminase 2 (TG2). It is possible that inhibition of TG2 may offer a therapeutic approach.

Individuals at increased risk for celiac disease include, in particular, 1st degree relatives of a celiac (risk 10-15%), individuals with type 1 diabetes mellitus (risk up to 9%) and autoimmune thyroiditis (risk up to 10%), and trisomy 21. 2nd degree and higher relatives also have a somewhat increased risk for celiac disease. In the case of 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), AK against tissue transglutaminase also occur. The tissue transglutaminase TG2 is the autoantigen of the anti-endomysial antibody (EMA).

The inflammatory process leads to apoptosis of enterocytes and villous atrophy. The consequence is a reduction of the absorption surface and resorption disorders.

Classical celiac disease

• This includes both affected persons with a "classic" enteric course and affected persons with "atypical symptoms", e.g. extraintestinal symptoms. Symptoms usually begin between the 1st and 3rd year of life. Classical celiac disease as gluten-induced enteropathy manifests with the disease signs of malabsorption such as weight loss, steatorrhea and protein deficiency edema. When the disease is fully developed, a distended abdomen, voluminous foul-smelling dyspeptic diarrhea, muscle hypotrophy, anorexia and changes in character (e.g., tearfulness) are already found in young children. In addition, iron deficiency or growth retardation are considered typical indications in childhood. However, the presentation of "classic" celiac disease has changed such that the classic infantile form is no longer the most common manifestation (Newnham ED 2017). Most affected individuals with symptomatic celiac disease are adults. They suffer from abdominal symptoms such as dyspepsia, flatulence, or change in bowel habits. Insomnia, fatigue, depression or constipation may also be symptoms. Not infrequently, laboratory chemical changes, such as a (mild) transaminase elevation or thyroid dysfunction, are the only indicators. The number of individuals diagnosed based on gastrointestinal symptoms is decreasing. The number of cases detected at screening (laboratory screening) of at-risk groups is increasing (Reilly N R et al 2011).

Symptomatic celiac disease

• Under the term "symptomatic or atypical celiac disease" constellations such as increased transaminases, neurological-psychiatric changes (e.g. migraine, epilepsy, depression), iron deficiency anemia as the most common symptom in adults, glossodynia, atrophic reddened tongue, osteoporosis, chronic hepatitis, arthritides are listed in affected persons. Furthermore as a well described clinical picture the "Dermatitis herpetiformis Duhring". 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 celiac disease (silenced celiac disease).

• Affected individuals with "asymptomatic celiac disease," have celiac disease-specific serology (including HLA DQ2/8 detection) and typical changes in small bowel biopsies (at least MARSH 2). They do not show any abnormalities even with careful history taking and physical examination as well as orienting laboratory diagnostics. After initiation of a gluten-free diet (GFD), no positive changes are usually observed. The now uncommon term "silenced celiac disease" has also been used for this situation. Individuals with asymptomatic celiac disease are usually identified through population-based screening programs, testing of first-degree relatives, or targeted searches for possible causes of comorbidities. Decreased quality of life or other minor symptoms such as extraintestinal manifestations (e.g., fatigue syndromes) may be signs of subclinical celiac disease.

Refractory celiac disease

• Refractory celiac disease (seen in approximately 1-2% of all celiac patients) is when intestinal or extraintestinal symptoms persist or recur despite evidence of new or persistent villous atrophy, despite a strict gluten-free diet for 12 months. The classification of refractory celiac disease into type I and type II is based on the characterization of infiltrating T cells, for which complementary immunohistological and molecular analyses must be applied. Whereas 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-assisted T-cell receptor analysis reveals T-cell clonality and immunohistochemical evidence of loss of surface antigens (CD3/CD8) in more than 50% of the intraepithelial T-cells. Immunohistology and molecular pathology are complementary in their informative value. T-cell clonality and aberrant immunophenotype indicate neoplastic transformation of T lymphocytes, but are not by themselves specific for refractory celiac disease and can also be observed - usually transiently - in uncomplicated celiac disease with gluten exposure. In contrast, the combination of a positive clonality finding and aberrant antigen expression has high specificity and predictive value with regard to the development of enteropathy-associated lymphoma (de Mascarel A et al. 2008) It is reasonable to assume that an EATL develops from an aberrant T-cell clone in refractory celiac disease type II.

Latent celiac disease

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

Potential celiac disease

• The term "potential celiac disease" applies to individuals who have a positive celiac disease-specific antibody constellation in serum. Histologic evaluation of the small intestinal mucosa reveals no pathologic 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 individuals with celiac disease-specific serology did not show any changes in the duodenum. Thus, potential celiac disease would be a relatively common clinical constellation (Biagi F et al. (2013).

Clinical symptoms:

• Motility disturbances, from diarrhea to constipation.
• Nausea and vomiting
• Flatulence
• Chronic abdominal pain
• Distended abdomen
• Weight loss
• Growth disturbance in the child
• Anemia (often iron deficiency anemia)
• Osteomalacia/osteoporosis
• Enamel changes
• Peripheral neuropathy/polyneuropathy
• Tetany/muscle weakness
• Night blindness
• Hematomas
• Edema
• Recurrent oral aphthae

Comorbidities:

Autoimmune diseases (Lundin KE et al 2015).

• Type 1 diabetes mellitus (celiac disease prevalence is reported to be 4.4% to 11% in pediatric and adult type 1 diabetics.
• 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 celiacs than in the normal population (about 2-3%).
• Irritable bowel syndrome (IBS): Affected individuals show an overall approximately 4-fold increased risk for celiac disease. Screening of IBS patients for celiac disease is reasonable. In persons with microscopic colitis, concomitant celiac disease is detected in about 5% of cases.
• Lactose intolerance

Neurological-psychiatric diseases:

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

Skin disorders:

• 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 celiac disease sufferers.
• Pyoderma

Genetic syndromes

• Down syndrome/trisomy
• Turner syndrome/monosomy X

Other diseases or symptoms or symptom complexes

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

Very sensitive serological antibody detections not only allow the diagnosis of celiac disease, but are also suitable for monitoring its course. The following antibody determinations 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 antibodies are very specific markers for the presence of celiac disease, and with the combination of these serological detections a high sensitivity and specificity can be achieved in the diagnosis of celiac disease.

Important: Up to 6% of coeliac patients suffer from IgA deficiency. In these cases, IgA-Ak determinationsare false negative and not useful. However, the IgG anti-transglutaminase 2 antibody remains positive. Therefore, total IgA should always be determined in parallel. If IgA deficiency is known, the IgG-Ak should be determined.

Additional testing for IgG antibodies against deamidated gliadin maximizes diagnostic sensitivity.

Important: Diagnosis should be made on a gluten-containing diet: Antibody titers drop on a gluten-free diet. However, the HLA markers remain positive. It is therefore necessary that the initial diagnosis be made on a gluten-containing diet. During the course of treatment, however, annual check-ups are 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 prerequisite for coeliac disease; 100% of coeliac patients carry one of these characteristics. The diagnosis of celiac disease is excluded in patients who do not carry these HLA traits. The HLA determination is not influenced by dietary measures.

Characteristic histological changes of celiac disease are:

• partial or total villi atrophy,
• Crypt hyperplasia,
• Changes in the villi/crypt ratio,
• increased mitosis in the crypts,
• increased intraepithelial lymphocytes (IEL),
• increased mitosis in the intraepithelial lymphocytes and
• an increased infiltrate of plasma cells, lymphocytes, eosinophil and basopil granulocytes in the lamina propria.

Marsh criteria in the histological evaluation of small intestine or duodenal biopsies:

• Marsh0: <25IEL/100 Enterocytes without crypt hyperplasia without villous atrophy
• Marsh1: >25IEL/100 Enterocytes without crypt hyperplasia without villi atrophy
• Marsh2: >25IEL/100 Enterocytes with crypt hyperplasia without villi atrophy
• Marsh3:
  • Marsh3a: >25IEL/100 Enterocytes with crypt hyperplasia, low to moderate villous atrophy11hie
  • 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 celiac 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-coeliac disease non-wheat allergy wheat sensitivity: wheat dependent clinic, mostly negative serology for celiac disease specific antibodies), normal small intestine histology, mostly negative specific IgE (wheat) and negative prick test (wheat); no malabsorption syndrome.

Drug-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 substitution: Hb deficit in g/l times 25 = total iron requirement in mg.
  • Oral: (Ferro sanol duodenal) 2(-3)times/day 50 mg, later 2(-3)times/day 100 mg p.o., preferably on an empty stomach. Infants 5 mg/kg bw/day p.o., divided into 3 EDs over 3 months.
  • Rarely intravenous (e.g., Ferrlecit): Adults 3.2-5.0 ml/day i.v. slowly.
  • Control: reticulocytes, Hb rise later. Continue to give until 3 months after normalization of blood count. Caveat. Do not administer simultaneously with tetracyclines, antacids, colestyramine, penicillamine.
  • Side effects include nausea, constipation, diarrhea, and blackening of the stool.
• Vit. B12 substitution (Neurotrat B 12): Induction with 1000-2000 μg/week i.m., i.v., or s.c. Reticulocytes increasing 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. for 4 weeks or 0.2 mg/day parenterally for 4 weeks.
• Vit. D substitution: Vit D3 (e.g. Dekristol, Vigantolettes) 5000-10,000 IU/day p.o. for 6 weeks, later 2000-50,000 IU/day for several months. Absolute calcium intake: 1 g calcium/day (4 times/day 250 mg p.o.).

Alternative: Oral endopeptidases, gluten-binding polymers, tTG inhibitors, HLA-DQ blocking peptides or various biologics (e.g. antiIL-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.

• Permitted foods:
  • Potatoes, rice, corn, amaranth, millet, all kinds of starch, also wheat starch, buckwheat, quinoa, soybeans, teff (millet type), chestnut, plantain.
• Not allowed food:
  • Wheat, oats, barley, rye, spelt, canoe, emmer, einkorn, green spelt, as well as all bakery/pasta products, bread, flour or flakes made from these grains.
  • Hidden gluten in sauces, soups, breakfast drinks, sweets, chewing gum, and finished products such as cake mixes
• Note: According to an EU directive, gluten must be displayed on finished products since 2004 and on counter sales since 2014. Today, many supermarkets offer a variety of gluten-free products. This makes it easier to find and consistently adhere 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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