Celiac disease: gluten enteropathy, symptoms and treatment

Celiac disease is an autoimmune disorder of the small intestine triggered by gluten (a protein found in wheat, rye, and barley) in genetically predisposed individuals (carriers of HLA-DQ2/DQ8). It is characterized by specific serology, varying degrees of mucosal villous atrophy, and a clinical response to a lifelong gluten-free diet. The disease can begin at any age and affect multiple organs, so clinical presentation ranges from "silent" forms to severe malabsorption. [1]

Over the past decade, diagnostics have become more accurate: the standard is antibodies to tissue transglutaminase IgA (anti-tTG IgA), with mandatory measurement of total IgA, confirmation by endomysial antibodies (EMA), and, if necessary, a duodenal biopsy. For children, according to the criteria of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), "biopsy-free" verification is permitted with high tTG IgA titers (≥10 upper limits of normal) and positive EMA in an independent sample. [2]

Understanding of immunopathogenesis has become more clear: tissue transglutaminase 2 deaminates gluten peptides, increasing their affinity for HLA-DQ2/8; this then activates T-cell responses, leading to inflammation with increased intraepithelial lymphocyte counts and villous damage. This has paved the way for targeted drugs (the TG2 inhibitor ZED1227 and others), which are in clinical development as dietary supplements. [3]

Celiac disease is associated with osteoporosis, iron deficiency anemia, hypertransaminasemia, infertility, neurological and skin manifestations (dermatitis herpetiformis), and, in refractory cases, with the risk of enteropathic T-cell lymphoma. Early diagnosis and a strict diet reduce complications and normalize quality of life. [4]

Code according to ICD-10 and ICD-11

In ICD-10, celiac disease is coded as K90.0 (celiac disease, non-tropical sprue, gluten-sensitive enteropathy). This code is used for a confirmed diagnosis; during patient management, codes for associated conditions (anemia, osteoporosis, hyposplenism, etc.) are added – this is important for routing, reporting, and payment of care. [5]

In ICD-11, diseases of the small intestine are classified in the DA90-DA9Z block; celiac disease itself is coded DA95 "Coeliac disease" (MMS version 2025-01). The ICD-11 system supports post-coordination (adding expanders), allowing for coding of organ manifestations and severity. This facilitates consistent coding across registries and studies. [6]

Table 1. Celiac disease codes in ICD-10 and ICD-11

Classification	Code	Name / Note
ICD-10	K90.0	Celiac disease (gluten enteropathy), includes "non-tropical sprue"
ICD-11 (MMS)	DA95	Coeliac disease; post-coordination by complications/organs is allowed

Epidemiology

The global prevalence of celiac disease in the population is estimated at approximately 0.7-1.4%: about 1.4% by serology and 0.7% by biopsy (meta-analysis). The rates vary by region: in Europe and Oceania - about 0.8% by biopsy; in North America - comparable; in South America - lower. The disease is more often detected in women. [7]

In Spain, the estimated prevalence is around 1% of the population, with age-specific differences: some studies have reported higher prevalence in children (e.g. 1:71 in children versus 1:357 in adults in early series), but current regional data indicate under-reporting and variability between autonomous communities.[8]

In first-degree relatives, the risk is significantly higher than in the general population: approximately 11% are serologically positive and 7% are biopsy-confirmed celiac disease (2024 meta-analysis of 34 studies). This justifies active screening in this group. [9]

Incidence trends in recent years show an increase in detection in adults and the elderly, while rates in children have stabilized, partly reflecting improved awareness and testing availability. The classic "malabsorption" pattern is becoming less common among new cases. [10]

Table 2. Epidemiological landmarks

Indicator	Grade
Global prevalence (serology/biopsy)	≈1.4% / ≈0.7%
Europe (biopsy)	≈0.8%
Spain (generally)	~1%, significant underdiagnosis
1st degree relatives	11% seropositivity; 7% biopsy-confirmed celiac disease

Reasons

The key cause is an immune reaction to gluten peptides (primarily gliadin) in HLA-DQ2 or HLA-DQ8 carriers. These major histocompatibility complex molecules present deaminated gluten peptides to T cells, triggering inflammatory cascades in the small intestinal mucosa. Without gluten exposure, the disease does not occur. [11]

The enzyme tissue transglutaminase 2 (TG2) plays a central role, deaminating gluten epitopes and increasing their affinity for HLA-DQ2/8. The production of antibodies to TG2 is the serological hallmark of the diagnosis. New drug developments (TG2 inhibitors) target this link. [12]

Along with HLA genes, numerous non-HLA loci contribute to innate and adaptive immunity. Microbiota, infections, and other environmental factors can modify risk and clinical phenotype, although their role is supportive. [13]

When gluten intake stops, inflammation subsides and the mucosa is restored, which confirms the cause-and-effect relationship and explains the effectiveness of the strict diet. [14]

Risk factors

The highest risk is in first-degree relatives (parents, children, siblings). A 2024 meta-analysis found that 11% are seropositive and 7% have confirmed celiac disease; daughters and sisters are most vulnerable. This justifies regular testing even without symptoms. [15]

Genetic syndromes (Down, Turner, Williams), autoimmune diseases (autoimmune thyroiditis, type 1 diabetes mellitus), IgA deficiency, and dermatitis herpetiformis are markers of increased probability. In these groups, a low threshold for screening is the standard. [16]

Female gender and European descent are associated with a higher prevalence, but celiac disease occurs worldwide and in all ethnic groups. Caution is important for "atypical" symptoms (anemia, osteopenia, elevated transaminases, neurological symptoms). [17]

In patients with irritable bowel syndrome, the incidence of celiac disease is higher than in the population: about 2% by biopsy (6% by serology), so testing is justified in the diarrheal or mixed subtype. [18]

Table 3. High-risk groups for targeted screening

Group	Approximate figures/notes
1st degree relatives	7% - biopsy-confirmed celiac disease
Autoimmune conditions	Thyroiditis, type 1 diabetes
Genetic syndromes	Down, Turner, Williams
Gastro-phenotypes	IBS-D/mixed subtype: up to 2% by biopsy

Pathogenesis

After gluten intake, its fragments (deaminated gliadin peptides) are modified by TG2 and bind to HLA-DQ2/8 on antigen-presenting cells; CD4+ T cells are activated, B cells produce antibodies (to TG2, EMA), and the number of intraepithelial lymphocytes increases. The result is inflammation, crypt hyperplasia, and villous atrophy. [19]

Over time, with continued gluten exposure, deficiencies (iron, folate, vitamin D), osteopenia/osteoporosis, transaminasemia, and neurological symptoms develop. A small proportion of patients may develop a refractory course with atypical T-cell clones. [20]

The fundamental idea of “trigger therapy” is supported by clinical observations and transcriptomic data: blocking deamination (TG2 inhibitors) or enzymatic degradation of gluten attenuates inflammation at the molecular and histological levels when provoked by gluten. [21]

Morphological changes are described according to the modified Marsh-Oberhuber classification (Marsh 0 to 3c) - from simple lymphocytosis to complete villous atrophy; however, interobserver variability requires a standardized biopsy technique and an experienced morphologist. [22]

Symptoms

Typical intestinal manifestations include chronic diarrhea, weight loss, steatorrhea, bloating, and abdominal pain. Many adults experience predominantly "non-intestinal" symptoms, including iron deficiency anemia, osteopenia/osteoporosis, impaired fertility, chronic fatigue, peripheral neuropathy, and depression. [23]

Mild and monosymptomatic variants are common: isolated anemia, persistently elevated transaminases, aphthous stomatitis, or dermatitis herpetiformis. The latter is practically pathognomonic: its presence is equivalent to celiac disease and requires the same approach. [24]

In children, growth retardation, bloating, chronic diarrhea, and, rarely, asymptomatic progression with positive serology are observed. It is important to recognize age-related factors and promptly seek testing if the IgA tTG titer is high. [25]

Red flags for suspected cases include: significant weight loss, dehydration, hypoproteinemia, resistant anemia, bloody stools (requiring an alternative cause to be sought), nocturnal symptoms, and fever - these should prompt prompt diagnosis and exclude concomitant diseases. [26]

Classification, forms and stages

A distinction is made between classical (malabsorption) and non-classical (predominantly extraintestinal) forms, as well as "silent" (screening detection without pronounced complaints) and potential celiac disease (positive serology without atrophy). This determines the approach to monitoring and re-evaluation. [27]

Histologic activity is described according to Marsh-Oberhuber: Marsh 1 - intraepithelial lymphocytosis; Marsh 2 - crypt hyperplasia is added; Marsh 3a-3c - villous atrophy stages. Control biopsy in adults is traditionally considered in cases of persistent symptoms and doubts. [28]

Refractory celiac disease (RCD) is the persistence of atrophy and symptoms for ≥12 months with proven dietary compliance; a distinction is made between RCD-1 (polyclonal IEL) and RCD-2 (aberrant IEL clones, with a poorer prognosis). These are rare but clinically significant variants. [29]

Table 4. Marsh-Oberhuber classification (simplified)

Step	Histological features
March 0	Norm
March 1	Intraepithelial lymphocytosis (>25-30 per 100 enterocytes)
March 2	+ Crypt hyperplasia
Marsh 3a-3c	+ Villous atrophy (partial → subtotal → total)

Complications and consequences

Failure to adhere to the diet can lead to persistent deficiencies (iron, folate, vitamin D/B12), osteoporosis and fractures, impaired fertility, adverse pregnancy outcomes, polyneuropathy, and cognitive complaints. Controlling inflammation reduces these risks. [30]

Refractory disease increases the risk of enteropathic T-cell lymphoma and small bowel adenocarcinoma; early identification of RCD-2 is critical for oncologic alertness and targeted treatment. [31]

Dermatitis herpetiformis, without diet, retains itchy blisters and erythema but responds well to strict diet; sulfones are used short-term as a bridge to the diet effect. [32]

Table 5. Common complications of celiac disease

System	Complications
Bone	Osteopenia/osteoporosis, fractures
Hematopoiesis	Iron deficiency anemia, folate deficiency
Neuro/psycho	Peripheral neuropathy, depression, cognitive impairment
Oncorisk (rare)	EATL, small bowel adenocarcinoma in RCD

When to see a doctor

You should seek immediate medical attention if you have severe diarrhea with dehydration, progressive weight loss, signs of malabsorption in a child, severe anemia, prolonged night symptoms and fever - this requires urgent examination and correction. [33]

A routine consultation is indicated in cases of persistent iron deficiency anemia without an obvious cause, osteopenia/osteoporosis, chronic diarrhea, elevated transaminases, dermatitis herpetiformis, and in the presence of first-degree relatives with celiac disease. [34]

Patients with established celiac disease should be consulted if symptoms recur, antibody titers remain high on diet, weight loss, night pain, or new extraintestinal symptoms occur - this may indicate gluten ingestion, underlying disease, or RCD.[35]

Diagnostics

Step 1. Serology against the background of gluten consumption. Test No. 1 - anti-tTG IgA plus total IgA; in case of IgA deficiency - tTG IgG/deaminated gliadin peptides (DGP-IgG). A positive result is confirmed by EMA IgA/IgG. Serology is performed BEFORE any diet. [36]

Step 2. Endoscopy with multiple duodenal biopsies. In adults with positive serology, the standard is histological confirmation (at least 4-6 biopsies from D2 + 1-2 from the bulb). The Marsh-Oberhuber assessment is used, taking into account the possible "mosaic" nature of the lesion. [37]

Step 3. "Biopsy-free" approach in pediatrics (ESPGHAN). In symptomatic children with IgA tTG ≥10 ULN and positive EMA in an independent sample, diagnosis is possible without a biopsy (with the correct test technique). In controversial cases, a biopsy is performed; if the results are inconsistent, a review of the slides/second opinion is sought. [38]

Step 4. HLA typing and additional testing. The presence of HLA-DQ2/DQ8 is necessary but not sufficient for diagnosis; the absence of these alleles makes celiac disease extremely unlikely. In “atypical” scenarios (long-term GFD prior to testing, potential celiac disease), HLA helps stratify risk. Screening for deficiencies and bone density assessment are part of the baseline evaluation. [39]

Table 6. Serological tests: what and when

Test	Role	Comments
anti-tTG IgA + total IgA	Screening No. 1 for adults and children	To do against the background of gluten
EMA IgA	Confirmation	High specificity
DGP-IgG	For IgA deficiency/in infants	Less specific in adults
HLA-DQ2/DQ8	Exclusive meaning	If HLA is negative, celiac disease is unlikely.

Differential diagnosis

It is necessary to differentiate from non-celiac gluten/wheat sensitivity (symptoms - yes, serology/biopsy of typical signs - no), lactase deficiency, irritable bowel syndrome, microscopic colitis, chronic infections of the small intestine and inflammatory bowel diseases. [40]

Iron deficiency anemia without diarrhea requires the exclusion of occult bleeding, HP-associated gastritis, and achlorhydria, but if there is no source, serology for celiac disease is indicated. If transaminases are elevated, viral hepatitis and fatty liver disease should be excluded; celiac disease remains a common "hidden" cause. [41]

In children, differentiation is made from functional disorders and food allergies; in adults, from IBS (celiac disease is more common in patients with IBS than in the general population). With Marsh 1-2, the range of alternatives is particularly broad, so a combination of serology, morphology, and clinical evaluation is important. [42]

Table 7. Celiac disease and mimicking conditions

State	What is similar	What makes it different
NCGH/wheat sensitivity	Pain, bloating, diarrhea	Negative tTG/EMA and biopsy
IBS	Pain/difficulty with stool	Normal serology/biopsy
Microscopic colitis	Watery diarrhea	Colon biopsies (lymphocytic/collagenous colitis)
Lactose intolerance	Bloating, gas formation	Association with dairy sugar-containing products

Treatment

The primary and only proven basic method is a strict lifelong gluten-free diet (GFD) excluding wheat, rye, and barley; most patients tolerate "pure" oats, but only if there is a guarantee of no cross-contamination. Dietary retraining is best done with a dietitian familiar with celiac disease: this increases adherence, reduces anxiety, and accelerates mucosal healing. Markers (tTG/EMA) should decline within the first 6-12 months. [43]

Nutritional support is essential: correction of iron, folate, vitamin D and B12 deficiencies, and calcium; densitometry in case of risk factors (postmenopausal women, long-term untreated disease). In case of severe malabsorption, gradual dietary rehabilitation is indicated; in case of hypolactasia, temporary lactose restriction. [44]

Monitoring includes clinical examination and serology every 6-12 months during the first year, then individually; in case of "non-response" to the GFD, hidden gluten intake is checked (dietary survey, search for traces of gluten in foods), concomitant conditions (microscopic colitis, SIBO, pancreatic insufficiency), and compliance with the regimen. Colonoscopy/repeat biopsy is considered as indicated. [45]

Refractory celiac disease (RCD-1) is treated "from simple to complex": open-label budesonide capsules (3-9 mg/day) for 3 months, followed by azathioprine 2-2.5 mg/kg if response is achieved; the goal is clinical and histological remission and steroid reduction. Monitoring includes bone tissue and infectious risks. [46]

RCD-2 requires management in a reference center: budesonide/systemic steroids are often combined with thiopurines; in the absence of a response, cladarabin, alemtuzumab, and other strategies are discussed under the supervision of a hematologist-oncologist. Screening and monitoring for EATL are mandatory. [47]

Dermatitis herpetiformis: strict GFD is the basis; for rapid control of skin manifestations, dapsone can be used at the minimum effective dose (under G6PD and hematological monitoring), then gradually withdrawn as the diet is effective. Long-term use of sulfones does not replace GFD. [48]

Novel and promising approaches: The oral TG2 inhibitor ZED1227 has been shown to reduce gluten-induced mucosal damage in a randomized trial and is supported by molecular transcriptomic data; the drug is being considered as an adjuvant to GFD to protect against adventitious traces of gluten. Further studies and optimization of formulations (TAK-227/variants) are ongoing. [49]

Enzyme preparations (latiglutenase/combined glutenases) have been shown to reduce gluten challenge injury and symptoms in subgroups in a number of studies, but results are heterogeneous; this is considered strictly an investigational/adjuvant approach and not a replacement for GFD.[50]

Intercellular junction density modulators (larazotide) failed to demonstrate efficacy in phase 3, and the pivotal study has been terminated; therefore, their use in routine therapy is not yet recommended. Patients should focus on diet and supportive nutritional strategies. [51]

Table 8. Management and treatment: “what, when and why”

Task	What are we doing?	Comments
Basis	Strict budgetary restrictions for life	With a nutritionist, tTG/EMA monitoring
Deficits	Iron, folate, vitamin D/B12, calcium	Risk densitometry
Non-responder	Diet revision, associated causes	If necessary, repeat biopsies
RCD-1	Budesonide → azathioprine	In the center with experience
New options	TG2 inhibitors (under investigation)	As adjuvants to GFD

Prevention

There is no specific primary prevention: HLA-DQ2/8 carriage is widespread, but the disease does not always manifest itself. The best "prevention of complications" is early detection and strict dietary management, especially in high-risk groups. [52]

Family education is important: first-degree relatives are offered serological screening even in the absence of symptoms, and if negative, retesting when complaints arise or every few years. [53]

Secondary prevention of complications includes correction of deficiencies, maintenance of bone mineral density, and age-appropriate vaccinations for hyposplenism. Regular consultation with a nutritionist reduces the risk of hidden gluten exposure. [54]

Forecast

With strict GFD, the prognosis is favorable: symptoms regress, serology normalizes, and the mucosa is restored in most patients within 12-24 months. Quality of life is comparable to the general population with high adherence and proper dietary therapy. [55]

Unfavorable factors include a long history of silent disease prior to diagnosis, poor dietary adherence, refractory forms, and concomitant autoimmune conditions. In these cases, the monitoring and treatment strategy should be more frequent and multidisciplinary. [56]

The advent of new adjuvant agents (TG2 inhibitors, etc.) may reduce the impact of random "traces" of gluten in the future, but they are not yet capable of replacing diet. Therefore, the role of patient and team (physician and nutritionist) education remains central. [57]

Table 9. What influences the forecast

Factor	Influence
Early diagnosis, strict GFD	Improves outcomes
High commitment	Fewer relapses/deficiencies
RCD-2, long-term late diagnosis	Worsens the prognosis
Comorbid autoimmune diseases	Require close monitoring

FAQ

Should everyone have a biopsy?
In adults, the answer is generally yes: positive serology plus biopsy remains the standard. In children, the ESPGHAN allows for a "biopsy-free" diagnosis with IgA tTG ≥10 ULN and confirmation of EMA in a second sample. [58]

How often should the diet be reviewed and antibodies monitored?
Typically, 6-12 months after starting the diet, and then individually. If antibody levels remain positive or symptoms persist, "hidden" gluten and associated causes are investigated. [59]

Is it possible to treat with "pills instead of diet"?
No. Oral medications are in development; TG2 inhibitors (e.g., ZED1227) have shown promise as an adjunct to diet, but not as a replacement. Larazotide has not demonstrated efficacy in phase 3. [60]

Which relatives should be tested?
All first-degree relatives, even those without symptoms. They have a 7% risk of biopsy-confirmed celiac disease; serology should be repeated periodically. [61]