Celiac Disease: Clinical Guidelines

List of Abbreviations

AGA – antigliadin antibodies

tTG – tissue transglutaminase

anti-tTG – antibodies to tissue transglutaminase

DGP – deamidated gliadin peptides

anti-DPG – antibodies to deamidated gliadin peptides

EMA – anti-endomysial antibodies

ESPGHAN – European Society for Paediatric Gastroenterology, Hepatology and Nutrition

HLA (Human Leukocyte Antigens) – a group of histocompatibility antigens, the human major histocompatibility complex

IgA – immunoglobulin A class

IgG – immunoglobulin G class

POC-test (Point Of Care Test) – a rapid test, a test strip for detecting antibodies to tissue transglutaminase in capillary blood

GFD – gluten-free diet

IEL – intraepithelial lymphocytes

SITM – small intestinal mucosa

Duodenum – duodenum

EGD – esophagogastroduodenoscopy

FPIES (Food Protein-Induced Enterocolitis Syndrome) – food protein-induced enterocolitis syndrome

AOECS – Association of European Coeliac Societies

Terms and Definitions

Haplotype - a set of alleles at loci on a single chromosome, usually inherited together

Heterodimer - a protein composed of two chains

Major histocompatibility complex - a group of genes and their encoded cell surface antigens (molecules) that play a critical role in foreign protein recognition and immune response development

Concordance - the presence of a given trait in both members of a twin pair or among a group of people. Concordance also refers to the probability that both twins will exhibit a particular trait given that one of them has it

Prolamins - a group of alcohol-soluble proteins found in the endosperm of cereal grains

Endosperm - tissue surrounding the developing embryo in a seed, providing it with nutrients

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Celiac disease – an immune-mediated systemic disorder that arises in response to the ingestion of gluten and related prolamins in genetically susceptible individuals, characterized by a wide combination of gluten-dependent clinical manifestations, elevated serum concentrations of specific antibodies (anti-tissue transglutaminase antibodies (anti-tTG), anti-endomysial antibodies (EMA), anti-deamidated gliadin peptide antibodies (anti-DGP)), the presence of HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy [1,2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The primary etiological factor in the development of celiac disease is gluten (synonym: gluten protein), a protein component of certain cereal grains. Toxic to patients are ethanol-soluble proteins of the grain endosperm of wheat (gliadins), rye (secalins), and barley (hordeins), which are collectively referred to in medical literature as "gluten".

Gliadins are polypeptide chains with a high glutamine and proline content, which determines their resistance to all gastric, pancreatic, and intestinal proteinases; their homologs are present in all cereals toxic in celiac disease and absent in non-toxic grains [3].

Currently, sufficient data have accumulated to regard celiac disease as a genetically determined condition. Among first-degree relatives of patients, the prevalence of celiac disease is 20%, and concordance among monozygotic twins reaches 86% [4]. The association of celiac disease with human leukocyte antigens (HLA) located on chromosome 6p21 has been proven. The HLA-DQ2 haplotype is detected in 90–95% of patients, and HLA-DQ8 in the remaining 5–10%. The absence of celiac disease-typical alleles in the genotype makes the development of the disease highly unlikely [5,6].

The central event in the pathogenesis of celiac disease is the presentation of gliadin peptides in the context of HLA-DQ2/DQ8 molecules to gluten-specific CD4+ T lymphocytes, followed by the development of an immune-inflammatory process in the small intestinal mucosa (SIM). An important role in the modification of gliadin peptides is played by tissue transglutaminase-2 (TG), an enzyme that catalyzes the deamidation of amino acids by replacing glutamine with glutamic acid. Under the action of TG, negatively charged epitopes are formed in the gliadin molecule, which increases the affinity of the peptides for the corresponding binding sites of DQ2 and DQ8 molecules and promotes tight binding of the HLA molecule with T-lymphocyte receptors (Fig. 1).

Fig. 1. Presentation of gliadin peptides to T lymphocytes in the context of HLA molecules (adapted from [7])

Activated CD4 cells produce pro-inflammatory cytokines (IFNγ, IL10, IL15, IL21) that damage enterocytes, and also stimulate B lymphocytes to produce antibodies against gliadin (AGA), tissue transglutaminase (anti-TG), and SIM structures (endomysium, EMA), which enter the systemic circulation and can be detected during serological testing (Fig. 2) [7,8].

Fig. 2. Immunopathological response in celiac disease (adapted from [9])

Pro-inflammatory cytokines can spread via the bloodstream far beyond the intestines; at the same time, the generated immune complexes can be detected both in the SIM and in other organs and tissues, including the liver, brain, peripheral lymph nodes, kidneys, and skin, which collectively determines the diverse (systemic) clinical manifestations of celiac disease.

Celiac disease can be considered a multifactorial disorder where, alongside genetic predisposition and the toxic effect of gluten, environmental factors play a certain role, the specifics of which continue to be studied.

1.3 Epidemiology of the Disease or Condition

Mass screening epidemiological studies conducted over the past 35 years using highly sensitive serological methods indicate that the prevalence of celiac disease in Europe and North America reaches 1% (1:100), with the ratio of diagnosed to undiagnosed cases being 1:5 to 1:13 [10]. An increase in disease frequency is supported by studies conducted in the Middle East, North Africa, South America, India, Australia, and New Zealand. According to a systematic review (2018), the global pooled seroprevalence of celiac disease-specific antibodies (anti-tissue transglutaminase and anti-endomysial antibodies) is 1.4%, while 0.7% of the global population has biopsy-confirmed disease. Table 1 shows the prevalence of celiac disease across different continents [11].

Table 1. Global prevalence of specific antibodies and biopsy-confirmed celiac disease [11]

In our country, mass epidemiological studies have not been conducted to date. The estimated prevalence of the disease in Russia may range from 1:100 to 1:250.

1.4 Features of Coding the Disease or Condition

K90.0 Celiac disease

K90.4 Intestinal malabsorption due to intolerance, not elsewhere classified¹

Note:

¹ – code may be used until the diagnosis is established

1.5 Classification of the disease or condition

In accordance with the clinical presentation and laboratory results, it was previously customary to distinguish the following forms of the disease:

Typical celiac disease, characterized by the presence of malabsorption symptoms in the clinical picture: chronic diarrhea, malnutrition, and deficiency states resulting from impaired absorption of minerals and vitamins;

Atypical celiac disease, in which gastrointestinal symptoms are absent or mild, while extraintestinal manifestations such as osteoporosis, anemia, infertility, and neurological symptoms come to the forefront in the clinical picture.

In both typical and atypical forms of the disease, the pathomorphological (histological) picture is characterized by atrophic enteropathy, and elevated levels of specific antibodies are detected in the blood serum.

Comment. Currently, dividing celiac disease into "typical" and "atypical" forms cannot be considered justified, since "atypical" forms are significantly more common than "typical" ones. When discussing the clinical presentation of celiac disease, it is currently more appropriate to distinguish symptomatic (with gastroenterological symptoms and/or extraintestinal manifestations) and asymptomatic forms of the disease. Patients with the asymptomatic (silent) form of celiac disease have no clinical manifestations whatsoever. In such cases, the diagnosis is established during screening examinations or when evaluating relatives/patients from risk groups.

If an elevated level of specific autoantibodies is detected in a child, in combination with the presence of HLA-DQ2/DQ8 alleles in the genotype, but in the absence of changes in the small intestinal mucosa (according to the pathologico-anatomical classification of enteropathy stages proposed by M.N. Marsh and modified by G. Oberhuber [see below in this section] — Marsh 0) or with minimal changes (Marsh 1), it is customary to speak of potential celiac disease [12]. Potential celiac disease can only be assessed by examining a sufficient number of small intestinal mucosal biopsy specimens. The management strategy for patients with potential celiac disease continues to be debated. According to the protocol proposed by Italian authors in 2019 [12], in the presence of symptoms, patients with potential celiac disease are strictly indicated to follow a gluten-free diet. In the case of an asymptomatic course of potential celiac disease, it is possible to continue monitoring the child on a regular diet with mandatory follow-up of the clinical picture, serial antibody level testing, and a repeat endoscopy with biopsy collection if elevated levels of specific autoantibodies persist.

Refractory celiac disease is characterized by a lack of response (clinical, serological, morphological) to a gluten-free diet. The refractory form of celiac disease (assuming complete exclusion of dietary indiscretions regarding gluten) is extremely atypical for children and necessitates further diagnostic workup.

Comment. It should be noted that distinguishing "primary" and "secondary" celiac disease, as well as "celiac syndrome," is categorically unacceptable. Celiac disease is always a primary disorder that currently has no radical cure. The aforementioned terms confuse both the physician and the patient, leaving open the possibility of being "cured" of celiac disease and, consequently, leading to the discontinuation of the gluten-free diet.

The following periods of the disease are distinguished: latent, clinical manifestation (active), and remission.

The latent period lasts from the moment of gluten introduction to the onset of clinical manifestations of the disease and can range from several days to many years. It is frequently undiagnosed and may be detected through targeted screening within risk groups.

The active period (period of clinical manifestation). (see section 1.6)

The period of incomplete remission (initial remission) develops, as a rule, 3–6 months after the initiation of a strict gluten-free diet; a decrease in the severity of main symptoms, a reduction in specific antibody titers, and the persistence of certain signs of atrophic enteropathy in the small intestinal mucosa are observed;

The period of full remission (clinical, serological, and morphological remission) is possible no earlier than 1–1.5 years after the start of a strict gluten-free diet and is characterized by the absence of specific antibodies and normalization of the morphological structure of the small intestinal mucosa.

If the gluten-free diet is not followed, the disease returns to the active period [8].

Pathologico-anatomical (pathomorphological, histological) classification of enteropathy stages

For the pathomorphological diagnosis of celiac disease, the classification of enteropathy stages by M.N. Marsh (1992) [51] was previously used, according to which 3 types of small intestinal mucosal damage are distinguished: type 1 (Marsh 1) — "infiltrative," type 2 (Marsh 2) — "hyperplastic," and type 3 (Marsh 3) — "destructive" or "atrophic" (Fig. 4).

Fig. 4. Types of mucosal damage according to M. Marsh's classification [51]

G. Oberhuber proposed a modification to M.N. Marsh's classification, pointing out the necessity of determining the number of intraepithelial lymphocytes (IELs) per 100 epithelial cells, as well as distinguishing 3 grades (A, B, C) of atrophic changes [52].

Currently, the Marsh-Oberhuber classification is most commonly used for pathomorphological diagnosis, which includes the following types of small intestinal mucosal damage (Fig. 5).

Fig. 5. Pathologico-anatomical classification of celiac disease according to Marsh-Oberhuber [52]

Along with the Marsh-Oberhuber classification, the Corazza-Villanacci classification [53, 54] and the Q-histological classification [55] can be used for the histological evaluation of enteropathy, which results in fewer discrepancies between specialists (pathologists) [56].

Duodenal atrophy (Marsh 3) is not a pathognomonic sign of celiac disease and can occur in a number of other conditions: post-enteritis syndrome; autoimmune enteropathy; immunodeficiency states (including AIDS enteropathy, common variable immunodeficiency); tropical sprue; radiation enteritis; use of certain medications (olmesartan); giardiasis; Crohn's disease; eosinophilic gastroenteritis; small intestinal bacterial overgrowth; Zollinger-Ellison syndrome; graft-versus-host disease; malnutrition; Whipple's disease; intestinal tuberculosis; in infants, enteropathy caused by cow's milk and soy protein allergy; and food protein-induced enterocolitis syndrome (FPIES) [57, 58].

An increase in the number of intraepithelial lymphocytes (IELs) is the earliest histological marker of celiac disease. Morphological changes in the duodenal mucosa begin with the infiltration of the epithelium by intraepithelial lymphocytes, resulting in enterocyte apoptosis. In the early stages (Marsh 1 and 2), the loss of enterocytes is compensated by crypt hyperplasia (where new enterocytes are generated), but as the disease progresses (when the reparative capacity of the crypts is exhausted), villous shortening occurs (Marsh 3a, 3b, 3c). As a result of a multicenter study using ROC analysis of IEL counts in over 400 duodenal mucosal biopsy specimens, it was established that an IEL count of > 25 per 100 enterocytes is diagnostically significant [59]. The use of immunohistochemical (IHC) methods (CD3/CD8 antibodies) to count IELs is not mandatory, but may be useful in the following cases:

1) in a patient with a high anti-tTG level whose histological picture corresponds to Marsh 0;

2) in the presence of a borderline IEL count;

3) when there is a suspicion of a lymphoproliferative disorder or the extremely rare refractory celiac disease type 1 or 2 in children [56, 60].

An increased number of IELs can be observed in various pathological conditions, in particular: viral, bacterial, and fungal intestinal infections, giardiasis, Helicobacter pylori infection, autoimmune enteritis, Crohn's disease, tropical sprue, common variable immunodeficiency, lymphoma, etc., as well as the intake of certain drugs (non-steroidal anti-inflammatory and antirheumatic drugs, olmesartan medoxomil, systemic hormonal contraceptives, etc.) [56].

1.6 Clinical presentation of the disease or condition

The most prominent symptoms of the disease are typically observed in children during the first years of life, with gastrointestinal manifestations usually dominating the clinical picture (Table 2).

Table 2. Clinical manifestations of celiac disease in infants and young children

In young children, celiac disease usually manifests 1.5–2 months after the introduction of gluten-containing products into the child's diet (rusks, bread, bagels, cream of wheat [wheat porridge], multi-grain porridge). Sometimes the manifestation of celiac disease in children occurs following infectious diseases (intestinal or respiratory infections), but the disease often starts without an apparent cause.

Clinical symptoms appear, in most cases, gradually. Copious, foamy, greasy, foul-smelling stools characteristic of celiac disease appear, along with appetite disturbances (food refusal or, conversely, increased appetite), unexplained vomiting, and weight loss. Parents note behavioral changes — irritability, negativism, and apathy appear, sleep is disrupted, interest in the surroundings disappears; the child may stop walking.

Older children complain of abdominal pain, which is usually intermittent and dull in nature and localized primarily in the periumbilical region. In adolescents and adult patients, the clinical presentation is more often characterized by a combination of intestinal and extraintestinal manifestations, with the latter frequently dominating [13, 14, 15, 16] (Table 3).

Table 3. Main clinical manifestations of celiac disease in older children

Comment. The clinical presentation of celiac disease lacks any single symptom occurring in 100% of patients, which frequently leads to diagnostic errors.

When celiac disease is suspected, one must remember its high frequency of association with a number of autoimmune and genetic disorders (Table 4).

Table 4. Diseases associated with celiac disease

Comment. Cases of celiac disease comorbidity with inflammatory bowel disease (ulcerative colitis and Crohn's disease), rheumatoid arthritis, psoriasis, multiple sclerosis, and Sjögren's syndrome have been repeatedly described, although not all authors recognize them as associated with celiac disease.

Patients with autoimmune and endocrinological diseases, certain chromosomal abnormalities, and first-degree relatives of patients with celiac disease should be classified as a high-risk group for developing celiac disease and require screening serological tests [1,2,13,17].

Considering published data indicating a high frequency of celiac disease among patients with cystic fibrosis, the possibility of screening for celiac disease in this category of patients should be considered. Particular attention should be paid to patients with low bone mineral density (BMD), patients with decreased BMD in the absence of other risk factors and/or vitamin D deficiency that is difficult to treat, as well as patients with persistent gastrointestinal disorders [18,19,20,21].

Comment: the development of celiac disease is impossible in children who have never received gluten-containing foods.

The development of celiac disease is impossible in infants receiving only breast milk and gluten-free complementary foods, even if the nursing mother consumes gluten-containing foods.

Timely detection of celiac disease and the prescription of a gluten-free diet in at-risk patients can prevent both the progression of the underlying disease and the development of severe, irreversible complications of celiac disease, including T-cell lymphoma and other malignancies (gastric and intestinal adenocarcinoma, esophageal squamous cell carcinoma). Therefore, selective screening in children within these risk groups should be considered justified.

Differential diagnosis of celiac disease is presented in Appendix A3.2.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diversity of the clinical presentation of celiac disease (ranging from severe malabsorption to extraintestinal, mild, and asymptomatic forms) makes it impossible to establish a diagnosis based solely on clinical manifestations.

It is important to perform screening tests for celiac disease not only in patients with characteristic gastrointestinal manifestations, but also in the presence of less pronounced extraintestinal symptoms, as well as among asymptomatic individuals, since even asymptomatic celiac disease can have negative consequences for a child's future health. Screening for celiac disease is indicated for:

• Patients with unexplained causes of chronic or recurrent diarrhea, growth retardation, weight loss, delayed puberty, amenorrhea, iron-deficiency anemia, nausea or vomiting, persistent abdominal pain, flatulence, persistent constipation, recurrent aphthous stomatitis, skin rashes, chronic fatigue syndrome, fractures from minor trauma / osteopenia / osteoporosis, or elevated transaminases on blood biochemistry;

• Asymptomatic patients at risk for celiac disease, in particular patients with type 1 diabetes mellitus, autoimmune thyroiditis, autoimmune liver diseases, selective IgA deficiency, Down and Turner syndromes, Williams syndrome, and first-degree relatives of patients with celiac disease.

Taking into account the high sensitivity and specificity of modern diagnostic methods, it should be borne in mind that currently there is no single study that can confirm the presence of celiac disease in a patient with 100% certainty. The diagnosis of the disease must be comprehensive and based on a joint evaluation of clinical data, results of serological, pathomorphological (morphological), and, if necessary, molecular genetic studies. Physician action algorithms are presented in Appendix B.

In 2012, the ESPGHAN working group developed a new protocol for diagnosing celiac disease in children [1], according to which a diagnosis of celiac disease can be established without performing a duodenal biopsy in children with characteristic symptoms of the disease, provided there is an elevated concentration of antibodies to tissue transglutaminase exceeding the upper limit of normal by more than 10 times, a positive titer of endomysial antibodies, and the presence of characteristic genetic markers in the patient.

Comments: reference values for antibody concentrations may vary among different diagnostic kit manufacturers.

In 2019, based on a large multicenter study conducted to evaluate the practical efficacy of the 2012 ESPGHAN protocol [22], the initial diagnostic algorithm was modified to omit mandatory genetic testing when diagnosing celiac disease without a small intestinal mucosal biopsy [17].

Criteria for establishing the disease: In accordance with the ESPGHAN 2019 recommendations [17], a diagnosis of celiac disease can be accurately established by a specialist (!) with or without a biopsy, provided that the relevant recommendations are followed (algorithms in Appendix B1 Physician action algorithm for suspected celiac disease in accordance with ESPGHAN 2019 criteria and Appendix B2 Algorithm for examining an at-risk patient for celiac disease in accordance with ESPGHAN 2019 criteria).

2.1 Complaints and Anamnesis

Patients with celiac disease may have various intestinal and extraintestinal manifestations of the disease; in some cases, celiac disease is asymptomatic.

Level of evidence 5 (strength of recommendation C)

Comment: celiac disease should be suspected in patients with the indicated complaints in the absence of another established cause for their occurrence. The decision on patient selection is made by the physician.

Level of evidence 5 (strength of recommendation C)

Comment: the decision on patient selection is made by the physician.

2.2 Physical Examination

Level of evidence 5 (strength of recommendation C)

2.3 Laboratory Diagnostics

Serological Diagnostics

Celiac disease is characterized by the appearance of specific antibodies in the serum, which include anti-tissue transglutaminase antibodies (anti-tTG), anti-endomysial antibodies (EMA), and anti-deamidated gliadin peptide antibodies (anti-DPG). Diagnostically significant is the detection of IgA class antibodies formed in the intestinal mucosa.

Level of evidence 5 (strength of recommendation C)

Comment: anti-tissue transglutaminase antibodies (anti-tTG) are determined by enzyme-linked immunosorbent assay (ELISA). The method is characterized by high sensitivity (98%), making it suitable for primary serological screening to select seropositive patients for subsequent endoscopic examination. The specificity of the method is also very high, although a slight increase in anti-tissue transglutaminase antibody titers is sometimes observed in patients with autoimmune and oncologic diseases, liver and cardiovascular pathologies, in children with persistent herpetic infection, widespread atopic dermatitis, and epidermolysis bullosa, which necessitates evaluating serological results in the context of the clinical situation. An isolated elevation of IgG anti-tissue transglutaminase antibodies in a patient with a normal serum IgA concentration is not a specific marker of celiac disease and requires a more in-depth diagnostic workup [16,23,28].

Immunoglobulin A level testing is performed to rule out false-negative serological results in patients with selective IgA deficiency [16,23].

For rapid diagnosis of celiac disease, point-of-care (POC) tests have been developed (tissue transglutaminase antibody IVD kit, immunochromatographic assay, rapid test), allowing the evaluation of anti-tissue transglutaminase antibody levels in patients' capillary blood within 10 minutes. This method uses endogenous transglutaminase present in blood erythrocytes as the substrate for antibody detection. Rapid tests can be used in outpatient settings for screening and selecting patients for further evaluation when celiac disease is suspected, as well as in risk groups.

To achieve optimal results as a screening tool, POC tests must have a high negative predictive value to avoid missed cases. It has been shown that the latest generation of rapid tests, which detect total IgA, IgG, and IgM antibodies against tissue transglutaminase, exhibit high sensitivity and specificity comparable to traditional determination methods (ELISA) [29].

A systematic review and meta-analysis conclude that the pooled sensitivity and specificity of modern POC tests in diagnosing celiac disease are very high. These characteristics allow POC tests to be used as a celiac disease screening tool, especially in areas with limited access to laboratory testing [11].

Nevertheless, a positive result on rapid tests requires confirmation using the standard celiac disease diagnostic algorithm; by itself, it is not a sufficient basis for diagnosing celiac disease or putting a child on a gluten-free diet.

Level of evidence 5 (strength of recommendation C)

Comments: diagnostic criteria for selective immunoglobulin A deficiency are in accordance with the clinical guidelines "Primary Immunodeficiencies with Predominant Antibody Synthesis Deficiency".

Level of evidence C (strength of recommendation 5)

Comments: the testing can be performed earlier if the child develops gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea, or changes in behavior and well-being [32]. A progressive increase in transglutaminase antibodies and/or the onset of symptoms is an indication for an endoscopic examination (esophagogastroduodenoscopy) with collection of duodenal mucosal biopsies (endoscopic small bowel biopsy), followed by lifetime pathomorphological examination of the biopsy (surgical) material of the fourth category of complexity without decalcification (see subsection 2.4).

Level of evidence 5 (strength of recommendation C)

Comment: in such a situation, an endoscopic examination (esophagogastroduodenoscopy) with collection of duodenal mucosal biopsies (endoscopic small bowel biopsy) is not required in most cases. It may be performed on an individual basis by agreement between the physician, legal representatives, and a child older than 15 years [16,23,28].

Anti-endomysial antibodies (EMA) also utilize tissue transglutaminase as their substrate, located in the extracellular matrix surrounding the smooth muscle elements of the lamina propria of the small intestinal mucosa. EMA are determined by indirect immunofluorescence. The method is semi-quantitative and has high sensitivity and specificity; however, it requires specialized equipment, and the interpretation of results is subjective and depends on the qualifications of the specialists.

Level of evidence 5 (strength of recommendation C)

Comment: in case of a positive result, the child should be referred for esophagogastroduodenoscopy with duodenal mucosal biopsy collection (endoscopic small bowel biopsy) and lifetime pathomorphological examination of the biopsy (surgical) material of the fourth category of complexity without decalcification (see subsection 2.4).

It should be noted that in clinical practice, the determination of blood anti-endomysial antibodies (class A immunoglobulin (IgA)) is poorly accessible; furthermore, the test results should be approached with caution, as their interpretation is subjective and depends on specialist qualifications, which can lead to underdiagnosis of celiac disease.

Level of evidence 5 (strength of recommendation C)

Comments: it is currently shown that anti-gliadin antibodies can be detected in patients with inflammatory bowel disease, various forms of food allergy, and even in some healthy individuals [14,15,16,17,23].

Antibodies to deamidated gliadin peptides (anti-DPG) may serve as a more specific marker of celiac disease compared to AGA. In terms of sensitivity and specificity, antibodies to deamidated gliadin peptides are not superior to anti-tTG and EMA. Anti-DPG (IgG) may add value to serological diagnostics, especially in children under 2 years of age in the case of total IgA deficiency and a negative anti-tTG (IgA) test result [22,23,28].

In patients with immunodeficiency states, celiac disease may occur without an increase in the level of specific antibodies, including IgG class. When following the appropriate diagnostic algorithm and thoroughly analyzing clinical data, morphological, and genetic diagnostic results, a diagnosis of seronegative celiac disease can be established [33,34].

2.4 Instrumental Diagnostics

The gold standard in diagnosing celiac disease in children is esophagogastroduodenoscopy (EGD) with simultaneous endoscopic duodenal biopsy and pathological anatomical examination of the duodenal biopsy (surgical) material.

In most cases, the endoscopic picture of the duodenum in children with celiac disease does not have any typical features. Celiac disease can be suspected during EGD based on macroscopic signs such as flattening or disappearance of circular folds of the duodenal mucosa, transverse striation of folds, honeycombing, or micronodular mucosal structure [35,36] (Fig. 3). At the same time, it is important to consider that these signs can also be observed in other diseases.

Fig. 3. Endoscopic signs of celiac disease

The macroscopic appearance of the duodenal mucosa may remain normal in 43% of children with celiac disease, which prevents endoscopic examination from being used as the primary diagnostic method [37]. It has become possible to increase the diagnostic value of endoscopy in patients with celiac disease by using modern high-resolution endoscopic technologies (NBI, zoom, immersion technique) [38,39,41].

Biopsy (endoscopic duodenal biopsy) during endoscopy followed by pathological anatomical examination is, in most cases, mandatory to confirm the diagnosis of celiac disease. Obtaining a sufficient number of biopsy specimens during the endoscopic procedure is necessary for high-quality morphological diagnosis of celiac disease, since focal atrophy of the small intestinal mucosa may occur in this condition; in such cases, a single biopsy taken from the duodenum may fail to reveal the histological changes characteristic of celiac disease [41,42,43].

Given the available data on the presence of isolated mucosal atrophy of the duodenal bulb in patients with celiac disease, taking a biopsy specimen from this zone is necessary during the endoscopic procedure [44].

Considering the patchy nature of atrophic changes, at least 4 biopsy specimens should be taken from the distal duodenum and 1-2 biopsy specimens from the duodenal bulb [45]. Taking a biopsy from the duodenal bulb makes it possible to diagnose celiac disease in 9.3 - 13% of patients who lack characteristic histological changes in the distal duodenum [46,47].

In real clinical practice, the number of biopsy specimens rarely reaches the recommended 5-6 [14].

According to research data, if anesthesia is not available and/or the biopsy quality is satisfactory and/or high-resolution microscopy is used, performing a biopsy from a smaller number of sites (2-4) is considered [48,49] with subsequent follow-up examination if necessary. At least one of the biopsy specimens should be taken from the duodenal bulb, as observations show that in 9–13% of patients, villous atrophy was observed exclusively in this section [50].

The complex of morphological changes in the small intestinal mucosa characteristic of celiac disease includes: an increased number of intraepithelial lymphocytes (IELs), varying degrees of villous atrophy, and crypt hyperplasia.

The modified Marsh scale [52] is used for pathological-anatomical (pathomorphological, histological) diagnostics (see section 1.5).

Diagnosing celiac disease requires interdisciplinary collaboration. For the correct interpretation of the pathological-anatomical (histological) picture, the pathologist must have access to anamnesis, clinical, endoscopic, and laboratory data [56,58,61].

The referral of the biopsy specimen for pathological-anatomical examination must include the following information:

- biopsy sites and number of biopsy specimens;

- exact fixation time of the biopsy specimens;

- whether the biopsy is diagnostic or performed for follow-up monitoring (e.g., after initiating a gluten-free diet);

- whether biopsy orientation was performed in the endoscopy room;

- brief medical history data (including information on whether the patient was on a gluten-containing or gluten-free diet);

- brief clinical data, including the results of serological testing;

- questions for the pathologist.

For the correct interpretation of the pathological-anatomical report data and establishment of the final diagnosis, the histological protocol must contain the following information:

- the pathological-anatomical description must be made separately for biopsy specimens from the distal duodenum and the duodenal bulb;

- biopsy orientation;

- villus shape and height;

- villus height to crypt depth ratio;

- number of IELs per 100 enterocytes;

- histological grading according to the Marsh-Oberhuber classification or others;

- a conclusion containing findings on the most likely diagnosis or range of diagnoses and, if necessary, recommendations for additional studies.

In cases where the diagnosis remains unclear after histological examination, it is advisable to organize an interdisciplinary discussion involving a gastroenterologist and a pathologist [56].

The detection of type 2 or 3A-C lesions upon microscopic examination is sufficient grounds for diagnosing celiac disease in seropositive patients, even in the absence of clinical manifestations of the disease.

The detection of an increased number of intraepithelial lymphocytes (Marsh-Oberhuber stage 1) upon light microscopy cannot serve as a basis for diagnosing celiac disease and requires additional studies, the results of which should be evaluated in conjunction with the clinical picture, serological test data, and, if necessary, HLA typing.

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comment: the diagnosis is subsequently confirmed by a decrease in antibody levels and a clinical response to a gluten-free diet.

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comments: in recent years, approaches to performing endoscopic duodenal biopsy in asymptomatic patients with a positive tissue transglutaminase antibody titer and no symptoms of celiac disease have undergone certain changes.

To avoid unnecessary biopsy in patients with low levels of specific antibodies (i.e., < 3 times the ULN) to tissue transglutaminase, testing for anti-endomysial antibodies is recommended (see subsection 2.3). If the result is positive, the child should be referred for an endoscopic examination (EGD) followed by endoscopic duodenal biopsy and histopathological examination of the duodenal biopsy specimen. If anti-endomysial antibody levels do not exceed the norm, repeat serological testing (see section 2.3) on a gluten-containing diet with an interval of 1–3–6 months is recommended [16].

Recent studies show that omitting endoscopic duodenal biopsy in the diagnosis of celiac disease can also be applied to asymptomatic children with high levels of specific antibodies to tissue transglutaminase. However, it should be borne in mind that the positive predictive value for specific anti-tTG antibodies (class A immunoglobulin) > 10 ULN may be lower than in symptomatic children.

In general, in asymptomatic patients, the possibilities of diagnosing celiac disease without biopsy are similar to those in patients with clinical manifestations of the disease [32].

Detection of type 2 or 3A–C mucosal damage upon microscopic examination is a sufficient basis for diagnosing celiac disease in seropositive patients, even in the absence of clinical manifestations of the disease.

The detection of an increased number of intraepithelial lymphocytes (Marsh–Oberhuber stage 1) upon light microscopy cannot serve as a basis for diagnosing celiac disease and requires additional studies, the results of which must be evaluated in conjunction with the clinical presentation, serological test data, and HLA typing.

Level of evidence 5 (strength of recommendation C)

Comment: it is believed that 3–6 months of gluten challenge is sufficient to induce changes in the jejunum characteristic of celiac disease. Conversely, excluding gluten from the diet can lead to the restoration of normal mucosal structure, making morphological confirmation of celiac disease difficult and sometimes impossible [32].

Level of evidence 5 (strength of recommendation C)

Comments: normally, in the duodenal mucosa, the villous height to crypt depth ratio is > 3:1, and the intraepithelial lymphocyte count is < 25 per 100 enterocytes; the lamina propria may show mild mononuclear infiltration (lymphocytes, plasma cells, histiocytes, mast cells) and eosinophils (up to 5 per high-power field) [61].

An objective assessment of the villous height to crypt depth ratio is only possible with proper orientation of the biopsy specimen (information regarding orientation must be included in the histological report) [23,56]. Oblique and tangential sections, as well as folded villi, can create a false impression of atrophy in normal mucosa [56]. It must be taken into account that normally villous height is lower over lymphoid follicles and Brunner's glands, which are located in the lamina propria of the duodenum (especially in the duodenal bulb). Therefore, the villous height to crypt depth ratio should not be evaluated over lymphoid follicles and Brunner's glands [58].

Level of evidence 5 (strength of recommendation C)

2.5 Other Procedures

Genetic diagnostics

Molecular genetic testing involves detecting the presence of characteristic HLA-DQ2/DQ8 alleles in the patient (Table 5).

Table 5. Variants of the HLA-DQ2/DQ8 genotype in patients with celiac disease

Negative results of genetic typing have a high negative predictive value, allowing celiac disease to be ruled out. At the same time, it should be noted that for correct interpretation of genetic test results, one must keep in mind the potential role of rare allele combinations (which include, for example, the HLA-DQ7 heterodimer encoded by the DQA1*0501-DQB1*0301 alleles), which may also determine the risk of developing the disease in certain patients [63,64].

It should be noted that the formation of the celiac disease phenotype, including the development of complications and treatment response, depends on both the influence of HLA family genes and non-HLA-dependent genetic variants. Studies by Russian scientists have demonstrated the involvement of several cytokine genes in the pathogenesis of autoimmune inflammation. Polymorphic variants of the IL1 (TDT=5.823; p=0.016), IL4 (TDT=12.000; p=0.001), and IL4RA (OR=7.42, p=0.006) family genes are associated with celiac disease. An association has been established between the G allele of the rs2243291 polymorphism in the IL4 gene (TDT=12.00; p=0.001) and the typical form of the disease, physical growth retardation (TDT=8.491; p=0.004), and decreased bone mineral density (TDT=12.023; p=0.001). A link has been found between the IL1RN gene and decreased bone mineral density (TDT=4.225; p=0.040), as well as between IL1B and physical growth retardation (TDT=3.841; p=0.050) [65,66,67].

The value of genetic testing is determined by the fact that its results do not depend on whether the patient is on a gluten-free diet at the time of testing or not.

The detection of celiac disease predisposition alleles during genetic testing does not indicate the presence of the disease, but merely places the patient in a genetic risk group, where diagnosis should be carried out in accordance with the above principles. At the same time, the absence of HLA-DQ2/DQ8 alleles in the patient's genotype allows the diagnosis of celiac disease to be excluded in 98–99% of cases. In dubious situations, the patient should be referred to an expert-level medical center.

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comment: the absence of HLA-DQ2/DQ8 genes in these patients in 98–99% of cases indicates that the child does not have celiac disease (including seronegative celiac disease) and determines the need to continue the diagnostic workup.

Level of evidence 5 (strength of recommendation C)

Comments: the absence of HLA DQ2/DQ8 haplotypes makes the development of celiac disease impossible in 98–99% of cases and allows gluten-containing foods to be returned to the child's diet. If symptoms appear during the gluten challenge, other forms of gluten-related conditions (non-celiac gluten sensitivity or wheat food allergy) should be considered.

Level of evidence 4 (Confidence level of recommendation C)

Comments: if predisposition alleles for celiac disease are detected in relatives, it is recommended to conduct appropriate laboratory diagnostic tests according to general principles (see clause 2.3). If an elevated level of specific antibodies is detected, a comprehensive evaluation should be performed in accordance with the recommendations presented in section 2.

Other diagnostic methods

Level of evidence 5 (strength of recommendation C)

Comment: if anti-tTG levels are elevated 10-fold or more and the EMA titer is positive, the diagnosis of celiac disease can be confirmed by a specialist without morphological examination, even in the absence of characteristic symptoms of the disease. With a smaller increase in the level of antibodies to tissue transglutaminase, the diagnosis of celiac disease requires mandatory endoscopic and histological examination (see subsection "Instrumental diagnostic methods") according to algorithm 1 (see Appendix B).

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comments: the challenge should be avoided during periods of intensive child growth [32].

During the gluten loading process, it is advisable not to include bread (cookies, baked goods) in the child's diet, because if the diagnosis of celiac disease is confirmed, re-restricting the child from consuming these foods will be very difficult.

Provocation test (gluten load)

Modern diagnostic protocols for celiac disease do not include repeated pathomorphological examinations or gluten loading. However, in practice, one has to deal with patients for whom a gluten-free diet was started in the absence of serological and morphological confirmation of the disease, or whose initial examination results cast doubt on the correctness of the diagnosis. In such cases, gluten loading is the only method to confirm the diagnosis.

Clarifying the diagnosis in patients with HLA-DQ2 and/or DQ8 alleles allows, after introducing gluten/gluten-containing products into the diet, assessing symptoms, examining the level of specific autoantibodies, and performing a pathomorphological (histological) examination.

The gluten challenge must be carried out strictly under the supervision of a gastroenterologist [32].

The daily dose during provocation should be at least 10 g of gluten [32], which corresponds to 150 g of flour or 200 g of wheat bread. Currently, it is believed that consuming 10-15 g/day of gluten for 3-6 months can induce small intestine changes in most children with celiac disease [32].

Gluten powder is scarcely available in Russian settings. Therefore, in practice, patients should be given 1 serving (approximately 250 g) of semolina porridge or wheat pasta/vermicelli daily.

• To avoid unnecessary gluten exposure in children with an early reaction to the provocation test, it is recommended to determine blood antibodies to tissue transglutaminase (IgA) 1 month after starting treatment, and subsequently every three months during daily gluten intake for 12 months [32].

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Diet Therapy

3.1.1.1 Gluten-free diet

The only treatment for celiac disease and the prevention of its complications currently is a strict lifelong gluten-free diet [8,13,16,69,70].

The diet composition for a patient with celiac disease depends on age, severity of the condition, and disease period, and is based on general principles: the carbohydrate component consists of well-tolerated cereals, potatoes, legumes, vegetables, fruits, and berries; protein and fat components come from meat, eggs, fish, dairy products, vegetable oils, and butter.

Level of evidence 5 (strength of recommendation C)

Level of evidence reliability 4 (conviction level of recommendation C)

Comment: elimination diet therapy is based on the complete exclusion of foods containing gluten or its traces from the diet. It is fundamentally important to avoid consuming not only foods containing 'obvious' gluten (bread, bakery and confectionery products, pasta, wheat/semolina, barley/pearl barley, bulgur, couscous, emmer, spelt, triticale, kamut) (Table 6), but also those containing 'hidden' gluten used as a food additive during manufacturing.

Table 6. Gluten-containing products and dishes that are strictly excluded from the diet in celiac disease

«Hidden» gluten may be present (depending on the manufacturer's recipe): 

• cooked sausages, wieners, minced meat and fish semi-finished products;

• many canned meat and fish products, especially in tomato sauce;

• many canned vegetables and fruits, including tomato pastes, ketchups, eggplant and zucchini caviar;

• ice cream, yogurts, curd desserts, curd cheeses and pastes, soft and processed cheeses;

• malt vinegar, certain types of salad dressings, Mayonnaises;

• dry seasonings and spices;

• concentrated dry soups, bouillon cubes, instant mashed potatoes;

• potato and corn chips;

• frozen French fries, certain types of frozen vegetables with added seasonings;

• certain types of tea, instant coffee and cocoa mixes;

• cornflakes, granola, breakfast cereals containing barley malt;

• seafood imitations — «crab sticks», «crab meat»;

• kelp salads with dressings;

• caramel, soy and chocolate candies with filling, oriental sweets, commercially produced jams;

Non-toxic grains in celiac disease include rice, buckwheat, corn, millet, amaranth, quinoa, montina, foxtail millet, sago, sorghum, teff, provided they are not contaminated with gluten during harvesting, transportation, storage, and processing. Flours and starches made from root vegetables (potatoes, cassava, tapioca, sweet potatoes), legumes (beans, lentils, peas, soybeans), and various nuts are safe.

The issue of oat toxicity in celiac patients remains open. The prevailing view is that oat avenins are non-toxic; however, oat groats are frequently contaminated with other grains, especially wheat.

Level of evidence 5 (strength of recommendation C)

Comment: trial inclusion of specialized (gluten-free) oats in the diet of celiac patients may be considered under strict control of clinical symptoms and specific serum antibody levels to enrich the patient's diet [76].

A small percentage of celiac patients may be sensitive to oats, developing symptoms and even small bowel mucosal damage upon consumption [76].

Comments: when planning their diet, celiac patients may use specialized gluten-free substitute products for bakery, pasta, and confectionery products. In these products, labeled as "gluten-free", the permissible gluten limit must not exceed 20 ppm* (20 mg/kg of finished product) [77].

When planning the diet of a child with celiac disease, it is necessary to account for secondary organ and system dysfunctions and deficiency states that may require specialized nutrition. The active period of celiac disease in early childhood is characterized by pronounced dyspeptic disorders and severe nutritional status impairments, up to severe protein-energy malnutrition (the so-called «celiac crisis»). Dietary management in such patients is complicated by the frequent development of multiple food intolerances. Most commonly, these are secondary lactase deficiency (75 %), sensitization to cow's milk proteins (72 %), and frequently sensitization to other dietary proteins such as rice, banana, chicken egg white, etc. Approximately 2/3 of young children with active celiac disease require the exclusion of dairy products and formulas alongside gluten. Dairy substitutes can include specialized formulas based on extensively hydrolyzed proteins enriched with medium-chain triglycerides, or amino acid-based formulas. However, the use of these products may be limited in patients with reduced appetite due to their specific organoleptic properties [69]. In severe malnutrition, factors such as marked anorexia and reduced tolerance to dietary loads must be taken into account. Nutrition during the active stage of the disease is conducted according to the principles of dietary management for children with protein-energy malnutrition [78].

It is widely believed that a number of non-food products that may enter the human body can also contain gluten. These include glue on postage stamps and envelopes, certain cosmetics including lipstick, certain toothpastes, etc.

Hygiene and cosmetic products, even those containing gluten, pose no danger to patients with celiac disease and dermatitis herpetiformis, since gluten causes adverse reactions in them only when it reaches the intestine, and is safe upon contact with the skin and oral mucosa. Toothpastes and lipstick are also safe for celiac patients, given the extremely small amount that could potentially be swallowed and reach the intestine [79].

Medicinal products may also contain gluten, including coated tablets.

Some medicinal products may contain wheat starch as an excipient. The European Pharmacopoeia limits the protein content in wheat starch to 0.3 % (3000 ppm), which corresponds to a gluten content of no more than 100 ppm [80]. Given the extremely negligible mass of the medicinal product a patient may consume per day, all medications registered on the European market can be considered safe and consumed by celiac patients, except in cases of individual hypersensitivity [79].

Certain food ingredients derived from gluten-containing grains, but processed to remove gluten, are considered gluten-free:

Glucose syrups made from wheat or barley, including dextrose;

Maltodextrin derived from wheat;

Distillates from gluten-containing grains, e.g., high-proof alcoholic beverages [81].

Patients require follow-up by a dietitian experienced in celiac disease to monitor strict adherence to the diet and the balance of the gluten-free regimen.

A gluten-free diet is not indicated for patients without celiac disease!!

3.1.1.1 Correction of nutritional deficiency

Level of evidence 5 (strength of recommendation C)

Comments: specialized formulas can be used both for sipping and for tube or gastrostomy feeding, depending on the severity of the patient's condition, the presence or absence of comorbid pathology, and the functional state of the gastrointestinal tract associated with celiac disease (Table 7).

Table 7. Specialized formulas for children with malnutrition associated with celiac disease

Note: ****Included in the Decree of the Government of the Russian Federation No. 3551-r dated December 11, 2023 "On Approval of the List of Specialized Medical Nutrition Products for Disabled Children" (as amended on November 1, 2025).

Level of evidence 5 (strength of recommendation C)

Comment: choice of drugs is individual, depending on the clinical situation.

3.1.2 Pharmacotherapy

Pharmacotherapy for celiac disease is of an auxiliary nature, but in a number of cases can be life-saving. It is mainly aimed at correcting deficiency states and metabolic disorders that have developed against the background of malabsorption syndrome.

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comment: indications are determined, inter alia, by a pediatric endocrinologist.

Level of evidence 5 (strength of recommendation C)

Comments: during the period of overt clinical manifestations of celiac disease, iodine deficiency and the formation of iodine-deficient goiter may also develop. The prescription and dose adjustment of iodine preparations, determination of the timing for monitoring thyroid profile hormones, as well as indications for replacement therapy in diagnosed thyroid disease fall within the competence of an endocrinologist.

3.2 Surgical Treatment

Not required.

3.3 Other Treatment

Patient School

Training in the "Celiac Disease Management School" leads to increased patient awareness, lower autoantibody levels, and disease compensation in a shorter time [89,90,91].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of evidence 5 (strength of recommendation C)

5. Prevention and Dispensary Observation

Prevention of celiac disease has not been developed.

Comments: previously held views that prolonged breastfeeding, the introduction of gluten-containing complementary foods in small amounts while breastfeeding during the "window of tolerance" (4–6 months), or delayed introduction of gluten reduce the incidence of celiac disease have been refuted in a number of multicenter randomized placebo-controlled trials [92,93].

5.1 Vaccination of patients with celiac disease

Preventive vaccinations are carried out during remission; celiac disease is not a contraindication for vaccination.

Patients with celiac disease have an increased risk of infections and reinfection/hospitalization, including due to malnutrition, increased intestinal permeability, and hyposplenism [94]; accordingly, vaccine prophylaxis in patients with celiac disease requires special attention.

To date, there is no convincing evidence linking vaccination to the subsequent development of celiac disease [95].

Contraindications to vaccination in patients with celiac disease do not differ from those in the healthy population [95]. In accordance with regulatory documents governing the procedure for selection for vaccination, any chronic disease is only a temporary contraindication to immunization during the acute phase [96]. During vaccination, patients with celiac disease should follow a gluten-free diet.

Level of evidence 5 (strength of recommendation C)

Comments: available data indicate that the immune response to most vaccines in children with celiac disease does not differ from that in the general population, and antibody titres are high enough to provide long-term protection [94].

Thus, for example, the immune response to vaccination against poliomyelitis, diphtheria, tetanus, measles, mumps, rubella, pertussis, Haemophilus influenzae type b, and influenza A (H1N1)09 in children with celiac disease is comparable to that in age- and sex-matched control children [97,98,99]. There is no convincing evidence supporting the need for regular checks of specific antibody concentrations against these pathogens in vaccinated patients during follow-up [32].

Contradictory data currently exist regarding the efficacy of vaccination against hepatitis A virus (HAV) in patients with celiac disease. A number of studies confirm that in the pediatric population of patients with celiac disease, the immune response to the hepatitis A vaccine is similar to that in control children [100]. At the same time, another study determined a lower immune response in patients with celiac disease vaccinated against hepatitis A [101]. These findings must be taken into account when monitoring patients with celiac disease, especially those living in regions endemic for hepatitis A.

Due to the fact that wild-type rotavirus infection has been identified as a potential risk factor for the development of celiac disease [102,103], the hypothesis exists that specific prevention of this gastrointestinal viral infection may play a positive role in preventing the development of celiac disease in risk groups. Studies have noted a trend toward a decrease in the incidence of celiac disease in the vaccinated cohort over 4–6 years of follow-up after vaccination [104]. A longer follow-up period (11–14 years) confirmed a significant reduction in the risk of developing celiac disease in childhood and adolescence among those who received specific prevention against rotavirus infection [105].

Level of evidence 5 (strength of recommendation C)

Comments: numerous studies have confirmed a significant decrease in the immune response to the recombinant hepatitis B surface antigen in patients with celiac disease following immunization [107,108,109,110,111]. Whether this is due to genetic non-responsiveness or other factors, such as gluten consumption, remains unclear [108].

To date, there are no direct indications that the level of antibodies to HBsAg requires constant monitoring during further patient follow-up; however, if the number of specific antibodies is reduced (in accordance with international standards — antibody titer < 10 IU/L), revaccination must be performed [32,94]. Revaccination with the hepatitis B vaccine** effectively induces adequate production of protective antibodies in children with celiac disease [94,107,112,113].

Level of evidence 5 (strength of recommendation C)

• Since celiac disease is the most common condition associated with functional hyposplenism, patients are advised to receive pneumococcal vaccination for prophylactic purposes [13,16,95].

Level of evidence 5 (strength of recommendation C)

Comments: World Gastroenterology Organisation global guidelines highlight the importance of preventive vaccination not only according to the universal immunization schedule, but also indicate the need for vaccination against pneumococcal disease, meningococcal disease, and Haemophilus influenzae b [114].

5.2 Follow-up care for an established diagnosis of celiac disease

Patients with celiac disease shall be placed on lifelong follow-up (dispensary observation).

Level of evidence 5 (strength of recommendation C)

Comments: follow-up is carried out until the patient transitions to adult care, and thereafter lifelong by "adult" specialists.

Level of evidence 5 (strength of recommendation C)

Comments: more frequently if necessary (persistence of symptoms, malnutrition, deficiency states, lack of positive dynamics in serological tests, etc.).

Given the high sensitivity and specificity of modern serological diagnostics, as well as the proven correlation between antibody levels and the degree of enteropathy, serial determination of blood anti-tissue transglutaminase antibodies plays a leading role in monitoring diagnosed patients [1,17].

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Level of evidence 5 (strength of recommendation C)

Comment: performed in a competent medical organization.

Level of evidence 5 (strength of recommendation C)

6. Organization of Medical Care

Patients with celiac disease may receive any type, conditions, and forms of medical care provided for by the legislation of the Russian Federation, as clinically indicated.

Primary specialized health care is provided by a gastroenterologist, dietitian, pediatrician, and other medical specialists.

Diagnosis of celiac disease can be performed on an outpatient basis:

- in patients with monosymptomatic/asymptomatic celiac disease when diagnostic facilities are available (EGD, serology, HLA typing);

- when the diagnosis can be established without pathomorphological (histological) examination in accordance with the 2012–2019 ESPGHAN protocols. However, the final diagnosis must be made by a specialist experienced in managing patients with this condition.

Indications for hospitalization of patients with celiac disease or suspected celiac disease are:

- need for complex invasive diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-care setting;

- need for diagnosis, treatment, and rehabilitation in an inpatient setting;

- presence of comorbid conditions or complications, etc., alongside celiac disease symptoms, requiring inpatient workup [13].

Children with mild and moderate celiac disease, if a diagnostic workup with combination therapy and evaluation of the effectiveness of a gluten-free diet is necessary, may receive medical care in a day hospital setting. Indications for admission to an inpatient or day hospital of a medical organization providing specialized medical care for celiac disease and suspected celiac disease are determined by a gastroenterologist, or in their absence, by a dietician or pediatrician (general practitioner / family physician). 

Indications for hospitalization to provide emergency and urgent medical care are:

- severe malabsorption syndrome (water and electrolyte balance disorders, severe malnutrition);

- other complications of celiac disease, including the presence of comorbid conditions, severe clinical course, and life-threatening conditions.

The organization of dietary nutrition for patients receiving inpatient care in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition".

Indications for discharging a patient from a medical organization are:

1. completion of the course of treatment or a stage of specialized medical care (including establishment of a diagnosis) in an inpatient or day hospital setting, provided there are no complications of treatment requiring drug correction and/or medical interventions in an inpatient setting;

2. refusal of the patient or their legal representative from specialized medical care in an inpatient or day hospital setting;

3. the need to transfer the patient to another medical organization of the appropriate medical profile. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a prior consultation based on the provided medical documents or a telemedicine consultation and/or a preliminary examination of the patient by medical specialists of the target medical organization.

7. Additional Information

Outcomes and Prognosis

Anti-relapse treatment: a strict lifelong gluten-free diet is the key to normalizing the structure and function of the small intestine, eliminating metabolic disorders, and ensuring normal physical, mental, and sexual development of the child. Additional drug therapy is prescribed based on individual indications.

Late diagnosis significantly increases the risk of serious complications such as infertility, osteoporosis, neurological disorders, and malignancies (particularly small bowel T-cell lymphoma). With strict lifelong adherence to a gluten-free diet, the prognosis is favorable.

With strict adherence to a gluten-free diet for more than 5 years, the risk of malignancies approaches that of the general population. The risk of autoimmune diseases (especially autoimmune thyroiditis and type 1 diabetes mellitus) and osteoporosis remains elevated, which must be taken into account during clinical follow-up (dispensary observation).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Averkina, Natalia Anatolyevna – Candidate of Medical Sciences, Gastroenterologist at the Gastroenterology Department, Federal State Budgetary Institution "Children's Medical Center", Member of the Union of Pediatricians of Russia.

2. Alexandrov, Timofey Leonidovich – Candidate of Medical Sciences, Researcher at the Department of Gastroenterology, A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health.

3. Anisimova, Inga Vadimovna – Candidate of Medical Sciences, Head of the Medical Care Organization Department, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Association of Medical Geneticists.

4. Balakireva, Elena Alexandrovna – Professor of the Department of Pediatrics, Doctor of Medical Sciences, Belgorod State National Research University (BelSU).

5. Baranov, Alexander Alexandrovich – Academician of the RAS, Professor, Doctor of Medical Sciences, Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health in NSC No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology at the N.F. Filatov Institute of Children's Health, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief Freelance Pediatrician of the Russian Ministry of Health.

6. Belmer, Sergey Viktorovich – Doctor of Medical Sciences, Professor of the Department of Hospital Pediatrics No. 2, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Vice-President of the Russian Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

7. Boraeva, Tatyana Temirbolatovna – Doctor of Medical Sciences, Professor, Head of the Department of Children's Diseases No. 1, North Ossetian State Medical Academy of the Russian Ministry of Health. Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists, Member of the Union of Pediatricians of Russia.

8. Borovik, Tatyana Eduardovna – Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, Chief Researcher at the Laboratory of Nutrition for Healthy and Sick Children, Dietitian at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor of the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Healthy Children Association, Association of Medical Geneticists, Russian Organization of Dietitians, Nutritionists and Food Industry Specialists, European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

9. Bugun, Olga Vitalievna – Doctor of Medical Sciences, Deputy Director for Clinical Work, Chief Physician of the Clinic at the Scientific Centre for Family Health and Human Reproduction Problems.

10. Bushueva, Tatyana Vladimirovna – Doctor of Medical Sciences, Chief Researcher at the Laboratory of Nutrition for Healthy and Sick Children, Dietitian at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor of the Department of Biochemical Genetics and Hereditary Metabolic Diseases at the Institute of Higher Education and Continuing Professional Development, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Healthy Children Association, Association of Medical Geneticists, Russian Organization of Dietitians, Nutritionists and Food Industry Specialists, European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

11. Bykova, Bella Alexandrovna – Candidate of Medical Sciences, Head of the Gastroenterology Department, A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health.

12. Gorelov, Alexander Vasilievich – Academician of the RAS, Professor, Deputy Director for Research at the Central Research Institute of Epidemiology of Rospotrebnadzor, Doctor of Medical Sciences, Professor of the Department of Children's Diseases, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

13. Gundobina, Olga Stanislavovna – Candidate of Medical Sciences, Leading Researcher, Gastroenterologist at the Research Institute of Pediatrics and Child Health in NSC No. 2 of the Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia.

14. Gurova, Margarita Mikhailovna – Doctor of Medical Sciences, Professor of the Department of Propaedeutics of Children's Diseases with a Course in General Child Care, Saint Petersburg State Pediatric Medical University, Leading Researcher at the Laboratory of Medical and Social Problems in Pediatrics of the Research Center of Saint Petersburg State Pediatric Medical University, Deputy Chief Physician for Medical Affairs at the Consulting and Diagnostic Center for Children, Academician of the International Academy of Ecology and Life Protection Sciences (IAELPS).

15. Dmitrieva, Yulia Andreevna – Candidate of Medical Sciences, Pediatrician, Gastroenterologist, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Associate Professor of the G.N. Speransky Department of Pediatrics, Russian Medical Academy of Continuous Professional Education.

16. Zakharova, Irina Nikolaevna – Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, Russian Medical Academy of Postgraduate Education of the Russian Ministry of Health, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

17. Zvonkova, Natalia Georgievna – Doctor of Medical Sciences, Associate Professor, Acting Head of the Laboratory of Nutrition for Healthy and Sick Children, Dietitian at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor of the Department of Pediatrics and Pediatric Rheumatology at the N.F. Filatov Institute of Children's Health, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Healthy Children Association, Association of Medical Geneticists, European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

18. Zvyagin, Alexander Alekseevich – Doctor of Medical Sciences, Professor of the Department of Propaedeutics of Children's Diseases and Polyclinic Pediatrics, Voronezh State Medical University named after N.N. Burdenko of the Russian Ministry of Health, Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.

19. Zokirov, Nurali Zoirovich – Doctor of Medical Sciences, Head of the Department at the Academy of Postgraduate Education of the Federal Scientific and Clinical Center of the Federal Medical-Biological Agency, Federal Scientific and Clinical Center of Children and Adolescents of the Federal Medical-Biological Agency, Member of the Union of Pediatricians of Russia.

20. Kaitukova, Elena Vladimirovna – Candidate of Medical Sciences, Deputy Head for Medical Activities – Head of the Consulting and Diagnostic Center for Children, Gastroenterologist, Leading Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health in NSC No. 2 of the Petrovsky National Research Centre of Surgery, Associate Professor of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia.

21. Kamalova, Aelita Asgatovna – Doctor of Medical Sciences, Associate Professor, Professor of the Department of Hospital Pediatrics, Kazan State Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia, Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

22. Klimov, Leonid Yakovlevich – Doctor of Medical Sciences, Professor, Head of the Department of Faculty Pediatrics, Dean of the Pediatric Faculty, Stavropol State Medical University.

23. Komarova, Elena Vladimirovna – Doctor of Medical Sciences, Deputy Head for Expertise of Innovative Treatment and Rehabilitation Methods, Gastroenterologist, Chief Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health in NSC No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia.

24. Kornienko, Elena Alexandrovna – Doctor of Medical Sciences, Professor, Head of the Department of Gastroenterology, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University, Saint Petersburg, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

25. Kondratyeva, Elena Ivanovna – Doctor of Medical Sciences, Professor, Head of the Scientific and Clinical Department of Cystic Fibrosis, Head of the Department of Respiratory Disease Genetics at the Institute of Higher and Additional Professional Education, Academician N.P. Bochkov Research Centre for Medical Genetics of the Ministry of Science and Higher Education of Russia, Deputy Director for Research and Head of the Cystic Fibrosis Center at the Research Clinical Institute of Childhood of the Ministry of Health of Moscow Region, Expert of the Diagnostics, Neonatal Screening, and Registry Committee of the European Cystic Fibrosis Society (ECFS).

26. Kutsev, Sergey Ivanovich – Academician of the RAS, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics, Chief Freelance Medical Geneticist of the Russian Ministry of Health, Chairman of the Profile Commission on Medical Genetics of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia, Moscow.

27. Elena V. Loshkova – D.Sc. (Medicine), Professor at the Department of Hospital Pediatrics and the Department of Faculty Pediatrics with a Course of Childhood Diseases at the Faculty of General Medicine, Siberian State Medical University; Leading Researcher at the Research and Clinical Department of Cystic Fibrosis, Research Centre for Medical Genetics named after Academician N.P. Bochkov; Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.

28. Andrey V. Naletov – D.Sc. (Medicine), Professor, Head of the Department of Pediatrics No. 2, M. Gorky Donetsk State Medical University of the Ministry of Health of the Russian Federation; Chief Pediatric Gastroenterologist of the Ministry of Health of the Donetsk People's Republic; President of the DPR Branch of the Union of Pediatricians of Russia; Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.

29. Leyla S. Namazova-Baranova – Academician of the RAS, Professor, D.Sc. (Medicine), President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery (NCC No. 2); Head of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health.

30. Valeriya P. Novikova – D.Sc. (Medicine), Head of the Department of Propaedeutics of Childhood Diseases with a Course of General Child Care, Saint Petersburg State Pediatric Medical University (SPbGPMU); Head of the Laboratory of Medical and Social Problems in Pediatrics, Research Center of SPbGPMU; Academician of the International Academy of Ecology and Life Protection Sciences (MANEB).

31. Nurniso D. Odinaeva – D.Sc. (Medicine), Professor, Director of the Research Institute of Childhood of the Ministry of Health of the Moscow Region.

32. Maria M. Platonova – Ph.D. (Medicine), Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery (NCC No. 2); Member of the Union of Pediatricians of Russia.

33. Dmitry V. Pechkurov – D.Sc. (Medicine), Professor, Head of the Department of Childhood Diseases, Samara State Medical University of the Russian Ministry of Health; Chief freelance pediatric gastroenterologist of the Ministry of Health of the Samara Region; Member of the Union of Pediatricians of Russia; Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.

34. Aleksandr S. Potapov – D.Sc. (Medicine), Professor, Chief Researcher at the Laboratory for the Development of New Technologies for the Diagnosis and Treatment of Childhood Diseases, National Medical Research Center for Children's Health of the Russian Ministry of Health; Professor at the Department of Pediatrics and Pediatric Rheumatology, N.F. Filatov Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of ESPGHAN; Member of the Union of Pediatricians of Russia.

35. Maria O. Revnova – D.Sc. (Medicine), Professor, Head of the Academician A.F. Tur Department of Outpatient Pediatrics, Saint Petersburg State Pediatric Medical University (SPbGPMU) of the Russian Ministry of Health; Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

36. Svetlana A. Repina – Ph.D. (Medicine), Medical Geneticist, Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov; Member of the Association of Medical Geneticists.

37. Elena A. Roslavtseva – Ph.D. (Medicine), Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

38. Lyubov V. Rychkova – Corresponding Member of the RAS, Professor, D.Sc. (Medicine), Director of the Scientific Centre for Family Health and Human Reproduction Problems, Irkutsk.

39. Liliya R. Selimzyanova – Ph.D. (Medicine), Head of the Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery (NCC No. 2); Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, N.F. Filatov Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

40. Irina V. Sichinava – D.Sc. (Medicine), Professor at the Department of Childhood Diseases, N.F. Filatov Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Union of Pediatricians of Russia.

41. Vera A. Skvortsova – D.Sc. (Medicine), Professor, Chief Researcher at the Laboratory of Nutrition for Healthy and Sick Children, Dietitian, National Medical Research Center for Children's Health of the Russian Ministry of Health; Member of the Children's Health Association and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

42. Andrey N. Surkov – D.Sc. (Medicine), Professor of the RAS, Head of the Department of Pediatric Gastroenterology in the Pediatric Hospital, Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery (NCC No. 2); Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

43. Rustem F. Tepaev – D.Sc. (Medicine), Head of the Anesthesiology and Intensive Care Service, Z.A. Bashlyeva City Children's Clinical Hospital; Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

44. Mikhail A. Tkachenko – Ph.D. (Medicine), Pediatrician, Gastroenterologist, Member of the Union of Pediatricians of Russia.

45. Alena A. Tyazheva – Ph.D. (Medicine), Associate Professor, Department of Childhood Diseases, Samara State Medical University of the Russian Ministry of Health; Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.

46. Anatoly I. Khavkin – D.Sc. (Medicine), Professor, Head of the Moscow Regional Center of Gastroenterology and Hepatology, Chief Researcher at the Department of Pediatrics, Research Institute of Childhood of the Ministry of Health of the Moscow Region; Chairman of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists; Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

47. Yury A. Shelygin – Academician of the RAS, D.Sc. (Medicine), Professor, President of the Association of Coloproctologists of Russia, Scientific Advisor, A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health, Chief freelance coloproctologist of the Russian Ministry of Health.

48. Ekaterina A. Yablokova – Ph.D. (Medicine), Associate Professor at the Department of Childhood Diseases, N.F. Filatov Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Union of Pediatricians of Russia.

49. Galina N. Yankina – D.Sc. (Medicine), Professor at the Department of Hospital Pediatrics, Siberian State Medical University of the Ministry of Health of the Russian Federation.

With the participation of a patient association representative:

Romanovskaya I.E. – Ph.D. (Biology/Pharm.), Associate Professor, President of the National Association of Organizations and Citizens Supporting Persons with Celiac Disease and Gluten Intolerance "Life Without Gluten"

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

These guidelines establish the types, scope, and quality indicators of medical care for children with celiac disease.

The clinical guidelines are based on a systematic literature review for 1990–2020 from Medline (PubMed version), Embase (Dialog version), and Cochrane Library databases, as well as international clinical guidelines for the diagnosis, treatment, and management of children with celiac disease.

The evaluation of the quality of evidence and the strength of recommendations for the application of medical technologies was performed in accordance with the standardized scale presented in Tables 1–3.

Target audience for these clinical guidelines:

1. Pediatricians;

2. Dietitians;

3. General practitioners (family physicians);

4. Gastroenterologists;

5. Endoscopists;

6. Pathologists;

7. Clinical laboratory diagnostics physicians;

8. Endocrinologists;

9. Dermatovenereologists;

10. Allergists-immunologists;

11. Trauma and orthopedic surgeons;

12. Pediatric oncologists-hematologists;

13. Medical students;

14. Residents and post-graduate students.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding diagnosis, treatment, prevention, and rehabilitation, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Regulatory documents

Care delivery pathways:

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On Approval of the Procedure for Providing Pediatric Care"

2. Information on medicines: https://grls.rosminzdrav.ru/

1. Other regulatory documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of the Russian Federation No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers";

4. Order of the Ministry of Health and Social Development of the Russian Federation No. 541n dated July 23, 2010 (as amended on April 9, 2018) "On Approval of the Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section 'Qualification Characteristics of Employee Positions in Healthcare';"

5. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Health Insurance in the Russian Federation' and the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding Clinical Guidelines";

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

7. Order of the Ministry of Health of Russia No. 804n of October 13, 2017, "On Approval of the Nomenclature of Medical Services";

8. Order of the Russian Ministry of Health (Ministry of Health of the Russian Federation) dated November 24, 2021, No. 1094n "On approval of the Procedure for prescribing medicinal products, prescription form templates for medicinal products, the Procedure for issuing said forms, their accounting and storage, templates of prescription forms containing prescriptions for narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents";

9. Order of the Ministry of Health and Social Development of the Russian Federation "On the procedure for using medicinal products in patients for vital indications" dated August 9, 2005, No. 494.

Appendix A3.2 Differential diagnosis of celiac disease

Differential diagnosis of celiac disease with other gluten-related disorders (wheat protein allergy, non-celiac gluten sensitivity), Table 1 [16,50].

Table 1. Differential diagnosis of celiac disease and gluten-related disorders

tTG - antibodies to transglutaminase, EMA - antibodies to endomysium, DGP - antibodies to deamidated peptides, AGA - antigliadin antibodies

Differential diagnosis of celiac disease considering clinical symptoms, Table 2 [16,50,115].

Table 2. Conditions requiring differential diagnosis with celiac disease based on clinical symptoms

Differential diagnosis of celiac disease from other conditions based on histological data (Tables 3, 4).

Table 3. Histopathological changes in other conditions that may require differential diagnosis with celiac disease [16]

Hp – Helicobacter pylori

NSAIDs – nonsteroidal anti-inflammatory drugs

PPI - proton pump inhibitors

Table 4. Diseases whose histological picture requires differential diagnosis with celiac disease [61, 117].

IEL – intraepithelial lymphocytes

NSAIDs – nonsteroidal anti-inflammatory drugs

MM – mucous membrane

Appendix B. Physician Action Algorithms

Appendix B1: Physician action algorithm for suspected celiac disease in accordance with ESPGHAN 2019 criteria

per [16] with amend.

Appendix B2: Algorithm for examining a patient at risk for celiac disease, in accordance with ESPGHAN 2019 criteria

per [16] with amend.

Appendix B2: Algorithm for performing EGD with duodenal biopsy followed by pathomorphological examination in the diagnosis of celiac disease, in accordance with ESPGHAN 2019 criteria

per [16] with amend.

Appendix C. Patient Information

What is celiac disease?

Celiac disease is a hereditary multisystem disorder characterized by atrophy of the small intestinal mucosa caused by exposure to gluten (a protein found in wheat, rye, and barley) and complete recovery of the mucosa upon the removal of toxic products from the diet.

The prevalence of celiac disease is high, estimated at 1 case per 100 individuals according to Central European data. The manifestations of celiac disease are individual; it is no coincidence that the medical literature refers to celiac disease as the "Great Mimic", as its presentations and complications vary depending on individual organism characteristics. Before diagnosis is established, each person with celiac disease has their own set of symptoms: some suffer from abdominal pain, others are plagued by diarrhea, while still others experience persistent constipation. Some complain of a lack of appetite, whereas others suffer from hyperphagia; there may be failure to thrive in weight and height, and some patients complain of bone pain. Spontaneous fractures, aggressive behavior, withdrawal, apathy, depressive states, severe headaches, migraines, pruritus, allergic skin and respiratory lesions, frequent viral infections, anemia, epistaxis, and even obesity can occur. If the diagnosis is not made in a timely manner, children and adults are followed for years by gastroenterologists, endocrinologists, dermatovenereologists, allergist-immunologists, trauma and orthopedic surgeons, pediatric oncologists-hematologists, and are repeatedly hospitalized in infectious disease, endocrinology, gastroenterology, allergology, traumatology, neurology, and even intensive care and psychiatric inpatient departments. In the presence of autoimmune and oncological diseases associated with celiac disease (such as autoimmune thyroiditis, rheumatoid arthritis, diabetes mellitus, autoimmune hepatitis, idiopathic cardiomyopathy, juvenile bleeding, chronic recurrent miscarriage, osteoporosis, small bowel lymphoma, gastric adenocarcinoma, squamous cell carcinoma of the esophagus, etc.), patients' quality of life deteriorates significantly and, accordingly, treatment costs increase manifold. Late-diagnosed celiac disease often leads to patient disability.

To correctly diagnose celiac disease, a comprehensive, phased, primarily laboratory examination is required. To confirm the diagnosis, esophagogastroduodenoscopy with histological examination of small bowel biopsy samples and genetic testing are frequently required. Timely diagnosis improves the quality of life.

Treatment of celiac disease

The only treatment for celiac disease is a strict, lifelong gluten-free diet, in which wheat, rye, barley, and products containing them are replaced by gluten-free cereals—namely corn, rice, buckwheat, millet, and other alternative gluten-free products. The patient must adhere to a gluten-free diet for life, as the intake of even 100 mg of gluten causes intestinal villous atrophy and the return of disease symptoms.

Upon establishment of the diagnosis, a new phase of the patient's life on a gluten-free diet begins—more social than medical.

The doctor has recommended a gluten-free diet for you

What do you need to remember?

1. There is no need to panic! It is better to treat yourself with food than with pills.

2. Gluten is a specific group of proteins found in wheat, rye, and barley. It provides elasticity and stickiness to dough, and softness and resilience to finished products. It is frequently used as a moisture-retaining and flavoring component in meat and fish semi-finished products and sausages. Gluten can be present overtly (in wheat, rye, and barley products), covertly (as an additive in semi-finished and industrially produced foods), and accidentally (for example, due to shared storage).

3. Always read the product label ingredients. Do not purchase a product if the ingredient list indicates: wheat flour, rye flour, barley malt, semolina, wafer crumbs, breadcrumbs, and other wheat, rye, and barley derivatives. Furthermore, products containing starch syrup, maltose, isomalt, maltodextrin, glucose-fructose syrup, and dextrose are not always safe.

Gluten-free products are labeled with the "crossed-out grain" symbol with

1. an alphanumeric code beneath it. Unfortunately, not all products currently labeled "GLUTEN-FREE" are actually free of it. Not all manufacturers test the raw materials used to make the product for gluten content. Do not hesitate to ask the manufacturer or representatives of patient organizations for celiac patients/parents of celiac children about the presence of gluten in a given product. They may have accurate information about both the product and its manufacturer.

2. Gluten may also be found in medications prescribed to you by your doctor. Don't expect your doctor to know the composition of every drug that exists in the world. Take the initiative and don't buy medications until you've checked their composition. Read about the additional components in the package insert included with each medication. Today, conscientious pharmaceutical companies carefully specify not only the composition of the drug itself but also the composition of its coating or capsule. What should raise your concern in medications? The presence of ingredients such as wheat flour, rice flour, all types of starch, wheat germ, and barley malt.

3. Social support for patients with celiac disease in the Russian Federation

Gluten-free products (cookies, pasta, bread made from rice or corn flour and starch, and other baked goods) are expensive. Their cost is 3 to 20 times higher than that of equivalent flour products.

Healthy Eating Pyramid.

The pyramid principle is nothing new in the world of healthy eating. For a healthy and balanced diet, our gluten-free pyramid is also divided into 4 groups:

1. grains

2. vegetables and fruits

3. dairy products, meat, fish, nuts

4. beverages, condiments, fats

1. Grains

At the base of the gluten-free food pyramid are products derived from grains: rice, corn, millet, buckwheat, and quinoa. So-called gluten-free products — bread, rolls, pasta, baking mixes, etc. — are produced from rice, corn, millet, and buckwheat specifically for people on a gluten-free diet.

Do not forget to check the ingredient list of products made from these grains, as you may encounter gluten-containing barley malt as an ingredient (it is frequently used in the production of corn puffs, corn flakes, and ready-to-eat breakfast cereals made from rice and corn balls).

Also exercise caution when purchasing ready-to-eat buckwheat and millet products. Unfortunately, testing of certain batches of prepared porridges from these grains has revealed high levels of gluten. Gluten contamination can occur due to improper storage or during the transportation of raw materials.

2. Vegetables and Fruits

All vegetables and fruits can be eaten. They are entirely gluten-free. For a proper, balanced diet, they should be diverse and consumed evenly throughout the day. The main thing is that they must be natural! They can be stewed, boiled, fried, baked, or grilled.

BUT: no breading, no batter, no sauces containing added flour. Note that vegetable bases for certain soups (such as traditional Russian shchi or borscht), according to standard recipes in restaurants, cafes, and canteens, are usually sautéed with flour.

Dried fruits are often treated with flour paste to protect against mold, so thorough soaking and repeated rinsing are recommended;

Frozen vegetables, fruits, and berries can be included in the diet. The exceptions are frozen French fries and complex prepared frozen meals.

Canned vegetables and fruits, including tomato pastes, ketchups, eggplant and zucchini caviars, and children's fruit-dairy and fruit-cottage cheese desserts, may contain wheat flour or semolina (depending on the manufacturer's recipe).

Protein-containing foods. Eggs, milk¹, fermented dairy products (kefir, sour milk, ryazhenka), butter, natural cottage cheese, natural sour cream, hard cheese, meat, poultry, fish, and seafood can be consumed without hesitation. Just like vegetables, we can prepare meat and fish in any way — stewed, boiled, fried, baked, or grilled.

"Hidden" gluten may be found (depending on the manufacturer's recipe) in boiled sausages, wieners, meat delicacies, minced meat and fish semi-finished products, and many canned meat and fish products, especially in tomato sauce. Seafood imitations — "crab sticks" and "crab meat" — generally contain gluten.

¹ Whole milk may cause abdominal bloating, flatulence, abdominal pain, and loose stools in some patients with celiac disease. This is due to insufficient activity of the enzyme lactase, which is typically reduced during the first 6 to 12 months after starting a gluten-free diet (GFD). Lactase activity recovers as the normal structure of intestinal villi is restored under the influence of the GFD. However, some people retain lactose intolerance, which is a hereditarily determined primary hypolactasia (in adults). Lactose-free milk is produced for such individuals. As a rule, they tolerate small amounts of fermented dairy products (100 – 150 ml per serving). Hard cheeses, "dry" cottage cheese, and butter contain virtually no lactose.

Which dairy products might raise doubts for us?

Cottage cheese mass, cheese product, certain yogurts (especially those with fruit fillers), and curd and processed snack cheeses. Unfortunately, for one reason or another, some manufacturers add flour or starch to the composition of these products. Flour can also be found in cottage cheese, sour cream, and even milk (more commonly from private sellers at markets).

All nuts — almonds, walnuts, Brazil nuts, peanuts, etc. — are gluten-free. Pay attention to coated nuts — wheat flour is often used to "make" salt or sugar adhere to the nuts.

Legumes — beans, peas, lentils, soybeans, chickpeas, mung beans, etc. — are a valuable source of plant protein. Legumes and flour made from them do not contain gluten. However, they should be avoided during the first few months to a year of a gluten-free diet, as the complex carbohydrates they contain can increase flatulence and even diarrhea.

3. Beverages, Condiments, Fats

At the top of the gluten-free nutrition pyramid, we have placed beverages (tea, coffee, cocoa), including sweet drinks (juices, fruit mors), vegetable fats, and condiments.

TEA

Traditional simple tea — black or green — is made from the leaves of the *Camellia sinensis* plant, which does not belong to gluten-containing grains. Thus, regular tea is gluten-free, provided it has not been cross-contaminated with gluten during processing. However, not all tea is made from *Camellia sinensis*, and there are varieties of tea (instant teas) that may contain barley malt as a sweetener, while there is also so-called "real" tea that features grain-based flavorings (most commonly from barley).

COFFEE

Natural coffee — whole bean, ground, or granulated — is gluten-free.

Coffee drinks, barley coffee, and cereal coffee contain gluten.

COCOA

Natural cocoa is gluten-free.

Instant cocoa, granulated cocoa, and cocoa drinks may contain gluten.

JUICES, FRUIT MORS

Natural juices, fruit mors, and beverages are gluten-free.

CONDIMENTS, SPICES, HERBS, SWEETS:

Single-ingredient unground condiments (1 ingredient) (dill, parsley, salt, pepper, onion, dried carrot, etc.) do not contain gluten.

One must be wary of any ground spices. Flour is added to spices (both store-bought and sold at markets) as an anti-caking agent and for cost-saving purposes. Attention! Soy sauces and all sauces based on them (such as Teriyaki) prepared according to traditional recipes contain gluten. Gluten may be present in: certain types of vinegars, salad dressings, and Mayones; concentrated dry soups, bouillon cubes, instant mashed potatoes; potato and corn chips; caramel, soy and chocolate candies with fillings, oriental sweets (e.g., churchkhela, kozinaki, Turkish delight), and industrially produced fruit preserves.

VEGETABLE FATS

Refined vegetable oil (olive, corn, soybean, sunflower, rapeseed, pumpkin seed, flaxseed, grape seed, walnut) is gluten-free.

The only vegetable oil strictly prohibited is wheat germ oil.

WHAT YOU NEED TO PAY ATTENTION TO:

1. Cross-contamination of food prepared at home with gluten. Gluten-free products for a patient with celiac disease must be stored separately from products for other family members, either in a separate cabinet or on a designated shelf.

A patient with celiac disease must have their own separate utensils for food preparation and eating, cutting boards, knives, colanders, sieves, etc., which should be stored away from the utensils of other family members. Some families prefer to follow a gluten-free diet together.

2. Purchased products labeled "gluten-free" and products bearing the "crossed-out grain" symbol without a registration number. Always check the product ingredients! The safest options are products whose packaging features the "crossed-out grain" symbol with a registration number (an alphanumeric code). Find the list of all Russian products with this symbol on the website перечеркнутыйколос.рф. View the list of products from foreign manufacturers on the website aoecs.org. International organizations have established the maximum allowable gluten content in gluten-free foods as < 20 ppm.

3. Consider your child's needs when preparing meals for the whole family. For example, when making pasta for everyone, boil a separate portion of gluten-free pasta for them. Try to ensure that your child follows the diet consciously. They must willingly agree to the need for dietary restrictions. Let them help prepare their porridge, school breakfast, and choose recipes for cakes and cookies to bake together with you. Do not allow the child even to taste forbidden foods, as these may later become a strong temptation. Grandparents and other older family members often become involuntary "adversaries" simply because they cannot imagine how their grandchild can grow up without bread. If you fail to explain the principles of the child's diet to relatives and acquaintances, ask your doctor to help. Teach the child how to respond to questions from friends about their diet. The desire to eat what classmates are eating can be very strong, but they will have to cope with it. Be sure to discuss this with the child before they start school. While it is undeniable that the child must be mindful of what they eat, this should not restrict other areas of their life. They should have opportunities to travel, participate in group activities, and play sports. Teach them to act in a way that makes them almost indistinguishable from healthy peers. Some children are completely unfazed by not being able to eat everything others do, while others feel deeply unhappy about it. Ultimately, a child's attitude toward their diet depends largely on adults—doctors, parents, and teachers.

EATING OUT:

Traveling:

When traveling independently, try to avoid hotels that offer a continental breakfast (unless it is strictly gluten-free). It is better to stay at a hotel with a buffet breakfast, as you can always find gluten-free options (vegetables, fruit, cheese, fish, etc.).

When booking a tour, be sure to request a gluten-free diet in advance with your tour operator for the hotel where you will be staying. Keep in mind, however, that very few tour operators truly understand what "gluten-free" means.

Out and About:

Are you or your child on a gluten-free diet? Plan your meals in advance when going for a walk around the city. Always carry allowed gluten-free snacks with you. Do not rely on being able to buy them along the way or grab a bite at the nearest cafe. Unfortunately, the menu often offers nothing gluten-free except tea or coffee. It is best to pack slightly more gluten-free food for the road than your child might actually need.

In Kindergarten:

If your city lacks a kindergarten with a gluten-free menu, look for other parents facing the same challenge, form a local community group, and petition your local education authorities to establish such groups.

At School:

How can you independently manage a schoolchild's diet? Unfortunately, nothing better than lunchboxes with sandwiches and thermoses for hot food has been invented yet. If you want your child to have hot meals at school and you trust the school kitchen, discuss gluten-free catering arrangements with the school administration and the cafeteria manager. VERY IMPORTANT!!! Discuss the child's diet with their teacher and classmates' parents. You don't necessarily have to scare them with an unfamiliar word like "celiac disease"; simply explaining it as a "flour allergy" is often enough. Coordinate the purchase of "safe" treats for class events, and it is usually best to take this responsibility upon yourself. Teach the child how to respond to questions from friends about their diet. The desire to eat what classmates are eating can be very strong, but they will have to cope with it. Be sure to discuss this with the child before they start school. Your child's diet should never prevent them from participating in class excursions, hikes, and field trips.

In Hospital.

During inpatient treatment, patients must be provided with necessary nutrition, medical care, and nursing care funded by the Mandatory Medical Insurance (OMI) system. If the hospital fails to provide gluten-free meals, contact your Territorial OMI Fund. Remember that middle-grade hospital staff (and frequently non-gastroenterologist physicians as well) are rarely familiar with "celiac disease" and a "gluten-free diet".

Purchasing Gluten-Free Products (Russian and Imported):

Trust only products bearing the "Crossed Grain" symbol and the registration number beneath it (an alphanumeric code). Such products undergo both industrial and public quality control. In addition to the symbol, the packaging may feature terms such as "gluten-free", "не содержит глютен", "glutenfrei", "glutenfri", "gliadinfri", "sin gluten", "sans gluten", or "senza glutine". Labels without the symbol are most often used for marketing purposes.

A list of guaranteed gluten-free products can be found on the crossedgrain.ru website (Russia) and the Association of European Celiac Societies website (aoecs.org).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.