Gluten-Free Diet, Symptom Burden, and Autoimmune Comorbidities: Insights from the Hellenic Celiac Disease Population

Abstract

Introduction: Living with coeliac disease (CD) requires lifelong adherence to a strict gluten-free diet (GFD). This study assessed GFD adherence, symptom burden, autoimmune comorbidities, and dietetic support among Hellenic CD patients. Methods: A cross-sectional survey was completed by 272 adults with CD. Adherence was measured using the Hellenic version of the Celiac Dietary Adherence Test (H-CDAT). Results: The mean H-CDAT score was 13.5 ± 3.5. Good adherence was observed in 44.9% of participants, while 14.3% showed poor adherence. Symptom burden was high: 39.3% reported partial symptom resolution and 3.7% had ongoing symptoms. Among patients, 25.0% had multiple autoimmune conditions, ranging from two to four. Dietetic support was limited: 61.5% were not referred to a dietitian at diagnosis, and 75.4% had no regular follow-up. Higher H-CDAT scores, indicating poorer adherence, were significantly associated with younger age (p = 0.014), earlier diagnosis (p = 0.01), and ongoing symptoms (p < 0.01). Age at diagnosis was also positively associated with autoimmune comorbidity count. Conclusions: These findings highlight the need for earlier diagnosis, improved access to structured dietetic support, and individualized care to optimize GFD adherence and improve outcomes in patients with CD.

1. Introduction

Celiac disease (CD) is an autoimmune disorder initiated by the ingestion of gluten, a storage protein naturally present in cereal grains such as wheat, rye, and barley [1]. In individuals with genetic susceptibility, particularly those who carry the human leukocyte antigen (HLA) DQ2 or DQ8 haplotypes, gluten exposure may lead to modification of gluten peptides by tissue transglutaminase (tTG) in the small intestine, inducing an inflammatory response that damages the small intestine’s mucosa and causes villous atrophy. Even a daily intake of 50 mg of gluten can cause deterioration and flattening of the intestinal villi, leading to reduced absorptive surface area and malabsorption of essential nutrients, notably iron, zinc, vitamin D, and B vitamins [1,2].

CD is estimated to occur in about 1% of the global population, and is becoming more frequently identified in developed countries due to improved awareness and advancements in diagnostic methods including serological, histological, and genetic testing [3]. CD is diagnosed more often in women, with reported female-to-male ratios varying from 2:1 to 3:1 [1]. While CD can appear at any age, it presents more frequently in adults than in children, with median age of diagnosis around 40 years [4].

Beyond nutrient deficiencies, CD is characterized by a highly diverse clinical presentation, encompassing gastrointestinal issues such as abdominal pain, diarrhea, constipation, and bloating [1,5]. Extra-intestinal effects, including tooth enamel defects, aphthous stomatitis, headaches, fatigue, depression, and anxiety, as well as neurological manifestations such as peripheral neuropathy, ataxia, and brain fog, are also common. Furthermore, CD can lead to serious long-term complications, including osteopenia, osteoporosis, infertility, anemia, and an increased risk of intestinal malignancies [6].

CD is increasingly recognized as part of a broader autoimmune spectrum and is frequently linked to other autoimmune conditions, most commonly type 1 diabetes and autoimmune thyroiditis [1,6,7]. Less frequently, CD coexists with autoimmune liver disease and autoimmune connective tissue disorders. This clustering of autoimmune diseases reflects shared genetic and immunological pathways, highlighting the need for comprehensive clinical management. Identifying and understanding the autoimmune comorbidities in patients with CD is essential for improving screening practices and providing better support strategies.

The only established treatment for celiac disease (CD) is the permanent and sustained elimination of gluten-containing foods, which helps alleviate symptoms and prevent long-term complications [1]. However, maintaining adherence to a gluten-free diet (GFD) may pose significant challenges, given the widespread presence of gluten in many foods, medications, and supplements [8]. Certified gluten-free products should contain no more than 20 parts per million (ppm) of gluten, in accordance with international standards, and are generally considered safe for most CD patients [9]. Nonetheless, careful reading of food labels remains essential to minimize the risk of gluten exposure.

Clinical guidelines recommend early referral to dietitians for patient education on label reading, gluten avoidance, and balanced nutrition, alongside ongoing follow-up to support long-term adherence and monitor nutritional status [6,10]. Nutritional counseling emphasizes the consumption of naturally gluten-free foods, including pseudocereals such as amaranth, quinoa, and buckwheat, cereals like maize, rice, and sorghum, as well as legumes, fruits, and vegetables [11]. It is worth noting that studies consistently demonstrate that many patients struggle with GFD adherence, with reported rates ranging from 45% to 90%, depending on the definitions and methods used for assessment [12,13].

In Greece, research on CD remains limited, and even less is known about the landscape of autoimmune disease, particularly clustering and co-occurrence patterns in this population [14,15,16,17]. In view of the above, this study aimed to robustly assess adherence to a GFD and map autoimmune comorbidities in Greek adults with CD, to examine their interrelation, as well as potential associations with dietetic support and other diet- and disease-related factors, providing insights that may inform clinical practice and improve patient care.

2. Materials and Methods

2.1. Study Design and Ethical Considerations

A cross-sectional survey was carried out through an online questionnaire, which was disseminated using Google Forms. It adhered to the ethical principles outlined in the Declaration of Helsinki and was approved by the Hellenic Mediterranean University Review Board in 2024 (Approval Number: 30922). Informed consent was obtained electronically from all participants. Participation was voluntary, and data collection was carried out anonymously to ensure confidentiality.

2.2. Questionnaire Design and Dissemination

The questionnaire was organized into domains covering demographic and clinical characteristics, GFD, CD-related symptoms, dietetic support, and the presence of coexisting autoimmune disorders. It was distributed nationwide via online platforms, including the Hellenic Celiac Society, hospitals, private clinics, support groups, and relevant social media channels. Questionnaire access was provided through a Google Forms link. The opening section of the questionnaire provided information regarding the study’s aims, and inclusion criteria. Participants provided informed consent by selecting a checkbox prior to beginning the survey. The survey was available from 10 December 2024 to 15 February 2025.

2.3. Participants

Inclusion criteria required participants to be adults (≥18 years) diagnosed with CD a minimum of one year before data collection. Exclusion criteria encompassed chronic illnesses including Alzheimer’s disease, malignancies, chronic kidney or pulmonary disease, and cardiovascular disease.

A total of 275 individuals responded. After applying the eligibility criteria, 272 participants, with age ranging from 18 to 72 years were enrolled in the study. Although there is no official registry for CD patients in Greece, given that CD prevalence is approximately 1%, this equates to around 100,000 CD patients nationwide [3]. A sample size of 272 participants is considered sufficient to provide insight into key trends within the Hellenic CD population.

2.4. GFD Adherence

Dietary adherence was assessed using the Hellenic Celiac Dietary Adherence Test (H-CDAT) [17]. The H-CDAT is a 7-item self-administered tool rated using a 5-point Likert scale. It evaluates four domains: CD-related symptoms (2 items), self-efficacy (1 item), motivations for maintaining a GFD (2 items), and perceived adherence (2 items). Total scores range from 7 to 35, with scores < 13 indicating good adherence, 13–17 moderate adherence, and >17 poor adherence.

The H-CDAT was recently validated in a representative sample of the Hellenic adult celiac population, demonstrating good internal consistency and construct validity, supporting its use in the present research [17].

2.5. Statistical Analysis

Data were analyzed using SPSS software (v.29; IBM Corp., Armonk, NY, USA). Qualitative variables were summarized using frequencies and percentages, while continuous variables were presented as means with standard deviations.

Differences in mean H-CDAT scores between two groups were examined using the independent samples t-test. For comparisons involving more than two groups and non-normally distributed data, the Kruskal–Wallis H test was employed. Correlations between continuous variables were assessed using Spearman’s rank correlation for non-parametric data and Pearson’s correlation coefficient for normally distributed variables. Statistical significance was set at a threshold of p < 0.05.

3. Results

3.1. Patient Profile

Overall, 272 patients were enrolled in the study, comprising 217 females (79.8%) and 55 males (20.2%). The mean age was 38.5 ± 11.6 years, and the mean age at diagnosis was 31.1 ± 13.5 years, range: 1–61 years.

Table 1. Overview of Patients’ Descriptive Characteristics.

	Characteristic	n (%)
	Gender (Female/Male)	217 (79.8)/55 (20.2)
	Member of Hellenic Celiac Society	104 (38.2%)
	First-degree relative with CD	3 (1.1%)
Marital status	Married or in a relationship	146 (53.7%)
	Single	97 (35.7%)
	Divorced	17 (6.3%)
	Widowed	2 (0.7%)
	Other	10 (3.7%)
Education level	Primary	4 (1.5%)
	Lower secondary	4 (1.5%)
	Upper secondary	45 (16.5%)
	Post-secondary diploma	33 (12.1%)
	University degree	117 (43.0%)
	Master’s degree	45 (16.5%)
	Doctorate	4 (1.5%)
Region of residence	Urban	219 (80.5%)
	Semi-urban	33 (12.1%)
	Rural	20 (7.4%)
Monthly income	<€500	45 (16.5%)
	€500–1000	102 (37.5%)
	>€1000	125 (46.0%)

CD: Celiac disease.

provides an overview of the patients’ descriptive characteristics.

3.2. Symptoms

Participants described a range of symptoms experienced before CD diagnosis, affecting both gastrointestinal and psychological domains (

Table 2. Reported Symptoms Before Diagnosis.

Symptom	n	%
Bloating/Abdominal pain	168	61.8%
Diarrhea/Constipation	152	55.9%
Fatigue	141	51.8%
Anxiety	90	33.1%
Vomiting/Weight loss	80	29.4%
Skin rashes	63	23.2%
Headaches/Migraines	60	22.1%
Brain fog	53	19.5%
Depression	47	17.3%

). Most prevalent were digestive issues, particularly bloating, abdominal pain, and diarrhea or constipation, followed by fatigue. Although less frequently, participants also reported extraintestinal manifestations, including depression, anxiety, headaches, and brain fog.

Regarding symptom burden, 44.1% of participants reported total resolution, indicating they no longer experienced symptoms. An additional 39.3% reported partial resolution, with fewer symptoms than before. Meanwhile, 3.7% continued to experience ongoing symptoms (no resolution), and 12.9% stated they had never experienced symptoms (

Table 3. Symptom Burden.

Symptom Burden	n	%
Total resolution	120	44.1%
Partial resolution	107	39.3%
No resolution (Ongoing symptoms)	10	3.7%
Never experienced symptoms	35	12.9%

).

3.3. Dietetic Support

Following diagnosis, 61.5% of patients reported that they were not referred to a dietitian/nutritionist by their doctor. Nearly half (46.7%) of patients had never visited a dietitian/nutritionist for GFD education. Regarding visits in the previous year, 89.0% reported no visits, 3.7% had one visit, 4.4% had two visits, and 2.9% had three visits. In general, 24.6% of patients reported being followed by a dietitian/nutritionist at least once every two years, while the majority (75.4%) had no regular follow-up (

Table 4. Referral, Visit Frequency, and Follow-Up Patterns with Dietitian.

Variable	Category	% (n)
Referral to dietitian	Referred	37.5% (103)
	Not referred	61.5% (169)
Ever visited dietitian	Never	46.7% (127)
	Once	36.4% (99)
	More than once	16.9% (46)
Dietitian visits in past year	No Visit	89.0% (242)
	1 Visit	3.7% (10)
	≥2 Visits	7.3% (20)
Follow-up frequency	At least once every 2 years	24.6% (67)
	No regular follow-up	75.4% (205)

).

3.4. Autoimmune Comorbidities and Clustering

Overall, 25.0% of participants (n = 68) had at least one autoimmune comorbidity beyond CD.

Table 5. Autoimmune Comorbidities Among Participants.

Condition	n	%
Celiac disease	272	100.0%
Hashimoto’s thyroiditis	51	18.8%
Psoriasis	6	2.2%
Rheumatoid arthritis	4	1.5%
Autoimmune hepatitis	2	0.7%
Multiple sclerosis	2	0.7%
Dermatomyositis	2	0.7%
Vitiligo	2	0.7%
Systemic lupus erythematosus (SLE)	2	0.7%
Psoriatic arthritis	2	0.7%
Graves’ disease	1	0.4%
Dermatitis herpetiformis	1	0.4%
Sjögren’s syndrome	1	0.4%
Alopecia areata	1	0.4%

presents a summary of autoimmune comorbidities. Most commonly reported were Hashimoto’s thyroiditis (18.8%), psoriasis (2.2%), and rheumatoid arthritis (1.5%), with several participants reporting multiple comorbidities. Specifically, 60 participants (22.1%) had two autoimmune conditions (including CD) and 7 (2.6%) had three. The maximum number of coexisting autoimmune disorders, including CD, was four, reported by a single patient (0.4%).

The clustering of autoimmune diseases along with CD was as follows:

• Hashimoto’s thyroiditis and psoriasis
• Hashimoto’s thyroiditis and autoimmune hepatitis
• Hashimoto’s thyroiditis and rheumatoid arthritis
• Hashimoto’s thyroiditis and psoriatic arthritis
• Hashimoto’s thyroiditis and vitiligo
• Psoriasis and psoriatic arthritis
• Hashimoto’s thyroiditis, systemic lupus erythematosus, and rheumatoid arthritis

3.5. Dietary Adherence

H-CDAT scores ranged from 7 to 23, with a mean of 13.5 ± 3.5. Males had a slightly lower mean H-CDAT score compared to females (13.09 ± 2.48 vs. 13.66 ± 3.68), with no statistically significant difference (

Table 6. H-CDAT Scores and Adherence Levels.

Group	Mean	±SD
All patients	13.5	±3.5
Males	13.09	±2.48
Females	13.66	±3.68
p-value	0.176
Adherence Level	n	%
Good (<13)	122	44.9%
Moderate (13–17)	111	40.8%
Poor (>17)	39	14.3%

). Good adherence was observed in 122 participants (44.9%), moderate in 111 (40.8%), and poor in 39 (14.3%).

3.6. Correlations and Group Comparison Analyses

A statistically significant negative correlation was observed between H-CDAT score and age (r = −0.148, p = 0.014), indicating that GFD adherence improves with increasing age. Additionally, a statistically significant negative correlation was found between H-CDAT score and age at diagnosis (r = −0.156, p = 0.01).

To assess the impact of symptom resolution on dietary adherence, a Kruskal–Wallis H test was conducted. A statistically significant difference in H-CDAT scores was observed across symptom-resolution groups (H = 19.55, p < 0.01), as illustrated in Figure 1. Patients reporting no symptom resolution had significantly higher H-CDAT scores (indicating poorer adherence) compared to those with partial or total symptom resolution.

A Kruskal–Wallis test was conducted to examine differences in GFD adherence based on the number of dietitian visits in the past year, categorized as no visits (n = 209), one visit (n = 10), and two or more visits (n = 18). A statistically significant difference in H-CDAT scores was observed across groups (χ² = 9.116, df = 2, p = 0.010). Mean H-CDAT scores increased with visit frequency: 13.33 for no visits, 15.40 for one visit, and 15.78 for two or more visits (Figure 2).

No statistically significant association was found between H-CDAT scores and the number of autoimmune comorbidities (p = 0.342). In contrast, a statistically significant positive correlation was found between age at diagnosis and the number of autoimmune comorbidities (r = 0.122, p = 0.045).

4. Discussion

The present study is the first to robustly assess GFD adherence in a nationwide sample of the Hellenic population with CD. H-CDAT scores revealed that good adherence was observed in approximately 45% of participants, aligning with the lower end of the 45% to 90% adherence range reported in the literature, and highlighting the persistent challenges in maintaining strict GFD [12].

Lower dietary adherence was significantly correlated with increased symptom burden among participants. This finding aligns with previous research demonstrating that poor GFD adherence is associated with persistent symptoms and poorer clinical outcomes in CD patients [18,19]. Additionally, a very recent study demonstrated that suboptimal adherence negatively impacts both physical and mental health-related quality of life, emphasizing the critical role of strict dietary compliance in improving patients’ overall health [17].

Furthermore, both current age and age at diagnosis were significantly associated with dietary adherence, in line with previous studies [18,20]. Younger and earlier-diagnosed patients often show lower adherence, likely due to social pressures, lifestyle factors, and less stable routines. In contrast, older individuals and those diagnosed later may demonstrate better compliance, possibly due to increased motivation and greater awareness of the health risks associated with non-adherence [12,21]. These age-related differences highlight the need for tailored educational and support strategies that address the unique challenges faced by different patient subgroups.

Interestingly, the study revealed substantial gaps in dietitian referral and follow-up. The majority of patients reported that their doctor did not refer them to a dietitian/nutritionist at the time of diagnosis, most lacked regular dietetic follow-up, and nearly half had never visited a dietitian/nutritionist for GFD education. These findings corroborate previous reports highlighting inadequate dietetic support as a major barrier in CD management [12,22].

However, H-CDAT scores did not show a significant correlation with dietitian referral, presence of regular follow-up, or total number of dietitian visits. In contrast, a group comparison revealed that H-CDAT scores differed significantly according to the number of dietitian visits reported within the previous year. More specifically, participants with two or more visits in the past year were more likely to have higher H-CDAT scores, indicating poorer adherence. Previous studies demonstrate that while dietitian involvement can enhance adherence, outcomes vary and are influenced by factors such as patient motivation, education quality, and the challenges of maintaining a strict GFD [23,24]. Our finding that increased dietitian visits are linked to poorer adherence may indicate that patients experiencing difficulties or persistent symptoms are more likely to seek frequent professional support.

Another key aim of this study was to map autoimmune comorbidities among CD patients, as this has not yet been explored in the Hellenic population. Our analysis revealed that one in four patients had at least one additional autoimmune comorbidity, with Hashimoto’s thyroiditis, psoriasis, and rheumatoid arthritis being the most prevalent. Our findings of a high prevalence of autoimmune comorbidities are consistent with previous studies that reported an increased risk of autoimmune disorders in individuals with CD [25,26,27]. This increased susceptibility is likely due to shared genetic, environmental, and immunological factors [28,29].

In our cohort of 272 patients, 8 met the criteria for Multiple Autoimmune Syndrome (MAS), a condition defined as the presence of three or more autoimmune disorders in a single individual [30]. This clustering of autoimmune diseases has also been reported among CD patients [31]. The highest number of coexisting autoimmune disorders found in our study was four (reported by a single patient), comprising Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, and CD. The identification of MAS cases underscores the importance of regular surveillance for the development of additional autoimmune diseases in celiac patients.

Notably, our study revealed a weak but statistically significant novel association between age at diagnosis and the number of autoimmune comorbidities, suggesting that delayed diagnosis and prolonged gluten exposure may contribute to additional immune-related complications. Despite ongoing debate regarding the impact of diagnostic timing on autoimmune risk [29,32,33], our findings align with literature emphasizing the benefits of timely diagnosis and strict adherence to a GFD in reducing symptom burden, preventing complications, and improving certain CD-associated autoimmune conditions [1]. Interestingly, emerging evidence from a recent systematic review indicates that a GFD may also benefit individuals with non-gluten-dependent autoimmune conditions, suggesting a broader role of gluten in immune regulation beyond CD [34].

The present study has certain limitations that warrant consideration. Its cross-sectional design limits causal interpretation of the observed associations. As an online survey, data were self-reported, which may introduce response bias. To minimize respondent burden, data on variables such as vitamin and mineral supplementation, medication use, smoking, or alcohol consumption were not collected. Additionally, recruitment through patient associations and online platforms may have introduced selection bias, potentially limiting the generalizability of the findings.

Prospective research is needed to better define the role of the GFD in modulating autoimmune risk and to examine how diagnostic timing may influence the development of autoimmune comorbidities in CD. Nevertheless, our findings corroborate prior research and provide meaningful insights into the nutritional implications of a GFD, extending its relevance beyond CD through the analysis of autoimmune comorbidities. The observed associations between age at diagnosis, dietary adherence, symptom burden, and the number of autoimmune comorbidities highlight the need for earlier detection, targeted education, and improved access to specialized nutritional care.

5. Conclusions

The present nationwide study revealed suboptimal adherence among the Hellenic CD population, which was associated with greater symptom burden. In addition, dietetic support was limited, with no referral at diagnosis and no regular follow-up reported by the majority of patients. A high prevalence of autoimmune comorbidities was observed, with the number of comorbidities linked to age at diagnosis. These findings highlight the need for earlier diagnosis, improved access to structured dietetic support, and individualized care to optimize GFD adherence and improve outcomes in patients with CD.