Celiac disease, an autoimmune condition, affects 48–300 million people worldwide [
1,
2]. For individuals with celiac disease, ingestion of gluten prompts an autoimmune response, damaging the structure and function of the small intestine and causing symptoms like headache, fatigue, skin manifestations, and neurologic symptoms [
3‐
5]. Managing celiac disease requires adherence to a strict gluten-free diet (GFD), which supports intestinal recovery and symptom relief for the majority [
6].
Despite optimal GFD adherence, 20–40% of adult patients continue to experience symptoms, and the cause for persisting symptoms is often unclear [
4,
7‐
14]. In a study including 99 U.S. adults with persistent symptoms on a GFD, the most common causes included ongoing gluten exposure (36%), co-occurring irritable bowel syndrome (IBS; 22%), and refractory celiac disease (13%), [
11], a finding replicated in 140 adult patients in Italy [
15]. Complete gluten removal from one’s diet may not be achievable, and even small amounts of gluten exposure can contribute to persistent symptoms and incomplete intestinal recovery [
16,
17]. Alternatively, persistent symptoms may indicate the presence of other food sensitivities or other medical conditions such as IBS, characterized by specific gastrointestinal symptoms (abdominal pain and bloating, painful bowel movements, and diarrhea and/or constipation) [
18,
19]. Women [
20]. and those with fewer years since diagnosis [
8] may be more prone to persistent symptoms.
Persistent symptoms in celiac disease are associated with worse physical functioning, impaired quality of life, and greater likelihood of anxiety and depression [
8,
12‐
14,
21,
22]. Furthermore, the severity of ongoing gastrointestinal symptoms [
23] is associated with reduced quality of life across specific domains (e.g., social functioning), greater anxiety, and depression [
14]. While a GFD helps some with anxiety and depression, for others, these symptoms persist or emerge even after intestinal recovery. The connections between these psychiatric symptoms and persistent physical symptoms is not well understood [
26].
Regardless of the underlying nature, persistent symptoms pose challenges in celiac disease management. Examining specific patterns of these symptoms and their associations with relevant clinical variables including disease factors, GFD adherence, psychiatric symptoms, and quality of life can offer insights into differential diagnosis and optimizing treatment. To date, no study has examined patterns of persistent gastrointestinal and extraintestinal symptoms and their relationships to these variables. The aims of this study were to use data available from the CureCeliac® research network to: [
1] identify patterns of persistent symptoms and subjective health ratings among U.S. adults with celiac disease; and [
2] examine whether persistent symptom profile groups report differences in GFD adherence, psychiatric symptoms, and quality of life and functioning.
Discussion
This study examined patterns of persistent symptoms and their relationships to disease management and wellbeing among U.S. adults with celiac disease. Four unique symptom profiles emerged. Profile 1, which comprised the largest proportion of the sample (37%), was characterized by overall low symptomology and excellent subjective health, but with persistent low energy and headaches. Profiles 2 and 3, the second (33%) and third (24%) largest, reported moderate overall symptomology, but differed from one another such that Profile 2 reported relatively greater extraintestinal symptomology and Profile 3 reported relatively greater gastrointestinal symptomology. Profile 4, the smallest profile (6%), was defined by the most severe symptomology across both extraintestinal and gastrointestinal symptoms, and was especially elevated in abdominal pain, nausea, stomach rumbling, bloating, partial bowel movement, and hunger pain compared to other profiles. Profile 4 was also consistently lowest in psychiatric wellbeing and various quality of life domains, consistent with literature showing that greater persistent gastrointestinal symptom burden relates to lower physical functioning, lower quality of life, and greater likelihood of anxiety and depression [
8,
22,
46].
Most research to date has examined gastrointestinal symptom burden and its relation to quality of life [
8,
22]. The present findings suggest that extraintestinal symptom burden may also impact quality of life and warrant intervention. Low energy, headaches, physical pain, and food cravings were present across all profiles, independent of gastrointestinal symptom severity. Research has shown that fatigue is common in adults with celiac disease and can persist despite GFD adherence [
47,
48]. In the present study, greater persistent fatigue co-occurred with greater psychiatric symptoms and worse social functioning. Profile differences in sleep disturbance followed a similar pattern. It is possible that improving sleep quality through interdisciplinary intervention approaches (e.g., cognitive-behavioral therapy for insomnia) may lead to reductions in fatigue and improvements in energy, psychiatric wellbeing, and functioning. Similarly, research has shown that headaches and migraines are common in adults with celiac disease and can persist despite GFD adherence [
48,
49]. Greater persistent headache appears to relate to greater psychiatric symptoms and role limitations.
Physical pain was endorsed to varying degrees across profiles, likely reflecting the high prevalence of bone and joint pain in celiac disease [
50]. Though single-item physical pain ratings varied between profiles, there were no profile differences on SF-36
bodily pain or PROMIS-29
pain interference. Given the known relationship between chronic pain, depression and anxiety, and lower quality of life [
51], some adults with celiac disease may benefit from adjunctive behavioral or medical intervention for managing headache and pain [
52]. Finally, additional research is needed to operationalize the experience of food cravings in adults with celiac disease and their impact on eating behavior and quality of life [
53].
Despite Profile 3’s moderate symptom burden and low subjective health as reported on the CSI, Profile 3 reported the lowest psychiatric symptoms and highest quality of life on standardized measures. Specifically, Profile 3 reported better general health, fewer role limitations due to physical health, less fatigue, and less sleep disturbance than all other profiles, and greater emotional wellbeing and better social functioning/ability to participate in social activities than Profiles 1 and 4. This finding suggests that overall symptom burden may not relate directly to worse wellbeing. Rather, specific symptoms might relate to wellbeing in different ways, and even patients with relatively lower overall symptom burden (e.g., Profile 1) may benefit from adjunctive interdisciplinary intervention to improve long-term outcomes. Additionally, patients such as those in Profile 3 may have coping skills or resilience factors that protect against deficits in psychiatric wellbeing and quality of life. Among adults with celiac disease, coping characterized by catastrophizing, emotional-oriented coping, lower perceived ability to decrease physical symptoms, and greater perceived difficulty following a GFD have been associated with lower quality of life [
23,
54,
55]. On the other hand, greater celiac-specific self-efficacy and lower risk perception have been shown to predict greater quality of life [
56]. Adjunctive behavioral treatment may be used to target these characteristics to increase psychiatric health and quality of life among adults such as those in Profiles 1 and 2.
There were no profile differences in self-reported GFD adherence, suggesting that differences in symptomology patterns might be explained by other factors, such as co-occurring IBS or other conditions, refractory celiac disease, or food sensitivities [
11,
15,
57]. However, because of possible bias in reporting using the CDAT, this finding is inconclusive without replication using objective measures of gluten consumption and standardized dietician interview. We also found no profile differences in celiac-specific quality of life as measured by the CD-QOL. There are no cut-offs on the CD-QOL to indicate whether the present sample had objective deficits in this domain.
Finally, there were no profile differences in current age, sex, race, age at celiac disease diagnosis, or years since celiac disease diagnosis, consistent with prior research, though findings have been mixed [
7]. However, Profile 4 reported lower household income and education level than Profiles 1 and 2. Income and education level are recognized social determinants of health that might influence symptomology and subjective health through mechanisms such as access to affordable gluten-free food, healthcare, specialty physicians, social support, and concomitant risk for gluten exposure [
58]. While this finding is preliminary and based only on a subsample that reported income and education information, further research is needed to explore the relationships between persistent symptoms and sociodemographic variables, especially given evidence for disparities in celiac disease diagnostic testing based on black race, coverage by public insurance [
59], male sex, and older age [
60], and the known relationship between food insecurity and heightened risk for gluten exposure [
61].
Strengths and limitations
To our knowledge, this is the first study to examine patterns of both gastrointestinal and extraintestinal symptoms in relation to celiac disease management and wellbeing, and the first to use LPA for this purpose. Our analysis examined a comprehensive range of potential risk factors and identified several potential intervention targets to support quality of life, and physical and mental wellbeing in adults with celiac disease. Further, this sample represents U.S. adults diagnosed with celiac disease across the lifespan with an average of six years since diagnosis, which offers insight into needs of patients beyond the initial diagnosis and follow-up period.
Despite these strengths, we acknowledge several limitations. For example, the CSI does not include all symptoms of possible interest. Assessment of gastrointestinal reflux, vomiting, and constipation may be important for ruling out various co-occurring functional gastrointestinal conditions. The present study also used a self-report measure to assess GFD adherence rather than a standardized dietetic assessment or objective measure of gluten intake (e.g., stool sampling). The CDAT assesses various aspects of gluten exposure risk but may not capture actual exposure. Future research should use standardized and objective measures that are less subject to reporting biases. Additionally, the present study selected participants who reported a diagnosis of celiac disease made by biopsy, serology, or genetic testing, which introduces the possibility of false diagnosis. Celiac disease is diagnosed in those with genetic predisposition when serology identifies elevated anti-tTG, anti-endomysium, and deamidated gliadin peptide antibodies, and/or histology finds evidence of duodenal villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Thus, the genotype HLA-DQ2 or HLA-DQ8 is a necessary but insufficient condition for diagnosing celiac disease, and best clinical practice is to make a diagnosis only after intestinal biopsy is performed. In clinical practice however, many individuals with celiac disease may not have undergone a biopsy or genetic testing due to various reasons, such as medical cost, accessibility, or patient preferences. We aimed to reflect the diversity of individuals living with celiac disease in real-world settings and to ensure that our study was inclusive and representative of a wide range of celiac patients, considering the heterogeneity in diagnostic pathways. Future studies may consider limiting analyses to the subset of individuals who reported a biopsy-confirmed diagnosis only.
Furthermore, participants in the present study were self-selected and represent a population with access to the internet, willingness to participate in research, and capacity to complete online questionnaires. Findings may not generalize to individuals with lower socioeconomic resources or those in otherwise marginalized groups. Additionally, higher base rates of persistent symptoms and quality of life concerns may be present in our sample given that individuals with those concerns may be more likely to seek online support and more likely to contribute information to the iCureCeliac® registry, a data gathering tool for researchers seeking to improve patient outcomes in celiac disease.
Most participants in the current study identified as female and non-Hispanic white, which reflects characteristics of the diagnosed U.S. patient population [
2,
4,
62‐
64] but may not generalize to other patient groups in the U.S. [
65] and abroad. The small size of Profile 4 may reflect the sociodemographic heterogeneity of the present sample, and findings should be replicated in a more racial-, ethnic-, socioeconomic-, and gender-diverse sample.
Conclusions
The prevalence and severity of persistent gastrointestinal and extraintestinal symptoms differ among adults with celiac disease. This study identified subgroups based on persistent symptomology, which differed in psychiatric wellbeing, functioning, and quality of life. Results suggest that lower overall symptom burden does not necessarily relate to better quality of life, and the relationship between persistent symptoms and wellbeing may be nuanced and depend on the specific symptoms and domain of quality of life assessed. Even patients with relatively low gastrointestinal symptom burden may nevertheless benefit from adjunctive treatment to address fatigue, pain, and headache, while those with other symptom profiles may not require the same. Additionally, coping skills may protect patients with greater gastrointestinal symptoms from negative quality of life outcomes. Future research should examine patterns of persistent symptoms that include a wider range of symptoms, use histological assessment and an objective measure of gluten intake to explore these relationships more robustly, assess both risk and resilience factors, and sample for sociodemographically diverse samples. This research will inform and improve healthcare for adults with celiac disease, serving to help identify patients most in need of additional support to optimize physical health and quality of life.
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