Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: a large cross-sectional study

At present, the only treatment for coeliac disease is a lifelong gluten-free diet, i.e. exclusion of wheat-, rye- and barley-containing cereals and food products. Upon removal of gluten from the diet clinical symptoms are usually rapidly alleviated, while recovery of the duodenal mucosa may take several months or even years [1]. The treatment may also prevent many coeliac disease-associated complications such as intestinal malignancies [2]. Notwithstanding these benefits, the stigma of a chronic disorder and the need for major dietary restrictions increases the self-perceived burden of illness and may impair patients’ quality of life [3, 4]. The symptoms may also remain despite a long-term and strict diet [5, 6]. As a result, in some studies even well-treated coeliac patients have failed to attain well-being similar to that of the population in general [7, 8], albeit that there are also contradictory results [9, 10]. To improve the situation, knowledge of the factors underlying these persistent health concerns in coeliac patients is required. Thus far, only a limited number of studies have investigated this issue [11]; data are scant, particularly in screen-detected patients and in subjects with extraintestinal presentation [9, 12].

The aim of this large nationwide study was to find predictors of persistent gastrointestinal symptoms and reduced health-related quality of life in long-term treated adult coeliac patients. Particular attention was devoted to aspects such as duration and severity of symptoms before diagnosis and presence of coeliac disease-associated and other co-morbidities.

Clinical characteristics of the study cohort are shown in Table 1. In total, 69% of the subjects were diagnosed on the basis of classical gastrointestinal presentation and 31% on the basis of extraintestinal symptoms or by screening in at-risk coeliac disease groups. Altogether 88% of the subjects were strictly adherent; none reported totally unrestricted gluten consumption and 82% used oats as a regular part of their diet. Lactose intolerance was present in 17%, food allergy in 5% and fructose intolerance in none of the participants. Further, 6% of the subjects had reflux disease, 4% gastritis, 2% diverticulosis and 2% cholelithiasis. The most common psychiatric disorder was depression, with a prevalence of 2% (78% of subjects with psychiatric diagnosis).

The mean total GSRS score was 2.1 (range 1.0- 4.8) in the study group and 1.9 (range 1.0- 4.2) in the controls. The score was higher than 1 SD compared to the control mean in 25% of the participants. There was no significant association between the persistent gastrointestinal symptoms and gender or current age, but patients diagnosed between the age of 25 and 60 years had more persistent symptoms than those diagnosed at younger or older age (Table 2). Further, subjects who had suffered from moderate or severe symptoms at the time of the diagnosis or had had symptoms more than 10 years before it had more current gastrointestinal symptoms than initially asymptomatic patients. Patients diagnosed on extraintestinal symptoms had fewer current symptoms than those with gastrointestinal presentation (Table 2). The presence of thyroid disease, non-coeliac food intolerance, other gastrointestinal disease and any coeliac disease-related co-morbidity also increased the risk of persistent symptoms. None of the other variables examined, including dietary non-adherence and consumption of oats, was associated with persistent symptoms. The GSRS mean total score was significantly higher in the study participants than in control subjects (p= 0.003).

The mean PGWB total score was 102.8 (range 29.0-132.0) in the study group and 105.3 (range 65.0-126.0) in the controls. Altogether 25% of the participants had the score lower than 1 SD compared to the control mean. Reduced health-related quality of life was seen in patients with manifest symptoms prior to diagnosis compared with asymptomatic subjects; the difference was evident in particular among those with symptoms for more than 10 years. Further, subjects with any psychiatric co-morbidity had reduced quality of life (Table 3). A similar trend was observed in patients with neurological disease and gastrointestinal co-morbidity, but the results in question were not statistically significant (Table 3). Of note, patients with persistent gastrointestinal symptoms were also more likely to have reduced quality of life (OR 4.66, CI 3.01-7.00, p < 0.001). The coeliac patients had lower mean PGWB scores than healthy subjects (p = 0.05).

The results of our nationwide study showed that up to 25% of adult coeliac disease patients suffer from persistent gastrointestinal symptoms despite a strict gluten-free diet. These findings show an excess of gastrointestinal complaints in treated coeliac patients, although to a somewhat lesser extent than noted in some previous studies [23, 24]. Yet it needs to be remembered that comparison between studies is difficult because both the methods to measure and definitions used for persistent symptoms may differ. Further, it is important to distinguish primary non-responsive patients from those investigated in the present study; common reasons for non-responsive coeliac disease are inadvertent gluten intake, refractory coeliac disease and concomitant diseases such as malignancies, microscopic colitis and pancreatic insufficiency [5, 25, 26]. Patients with any such concomitant condition or refractory coeliac disease were excluded from the present study. Furthermore, although no histological evaluation was undertaken here, judging from both dietary interview and serological testing the majority of participants were adhering strictly to the diet. It would thus seem unlikely that inadvertent gluten intake or presence of the aforesaid adjunct disease would explain the ongoing gastrointestinal symptoms.

In the present study, coeliac patients diagnosed at working age had more current symptoms than those diagnosed at an either younger or older age. Although we cannot confirm the reason for this age dependency of the symptoms, it is possible that changes in established dietary habits are more difficult to cope with simultaneously with other challenges encountered in daily work and family life. Likewise, for some unexplained reason, irritable bowel syndrome (IBS) often emerges in early adulthood [27]. Interestingly, also severe and long-lasting symptoms prior to diagnosis predispose coeliac patients to persistent symptoms. It has been suggested that such long-lasting abdominal complaints result in a chronic cycle of pain in consequence of changes in the gut-brain axis [28, 29]. Of note, similar chronic alterations have been hypothesized to be involved in the pathogenesis of IBS, which often co-exists with coeliac disease [30‐32]. There is also evidence suggesting that the symptoms in IBS might be caused by continuous low-grade small-bowel mucosal inflammation [30, 31, 33], a condition which may persist in coeliac disease despite a strict gluten-free diet [34, 35]. Finally, small-intestinal bacterial overgrowth may account for symptoms in both coeliac disease and IBS and is also accompanied by mucosal inflammation [33, 36, 37]. Whatever mechanisms lie behind the persistent symptoms, our results indicate that they could be ameliorated by diagnosing coeliac disease as early as possible.

The results obtained showed the presence of a coeliac disease-related co-morbidity, another gastrointestinal disorder or non-coeliac food intolerance to predispose to persistent symptoms. It is possible that concomitant gastrointestinal co-morbidity further reinforces the impact of the aforementioned long-lasting changes in the gut-brain axis. Interestingly, a particular association was seen between persistent symptoms and concomitant thyroid disease, which when untreated is known to may cause abdominal complaints, these usually recovering on treatment [38]. However, some patients evince persistent clinical symptoms and reduced health-related quality of life even while on treatment and euthyroid [39]. The pathogenic mechanisms underlying this remain unclear, but clearly the possible connection between thyroid disease and persistent gastrointestinal symptoms in coeliac disease calls for further investigation.

As was the case with gastrointestinal symptoms, a substantial proportion of the coeliac patients here showed reduced health-related quality of life while on a gluten-free diet. Again, long duration of symptoms before diagnosis was a predisposing factor. In contrast, there was no association between clinical manifestations of coeliac disease at diagnosis and current quality of life. This is in line with our previous results showing similar health-related quality of life in screen-detected and symptom-detected coeliac patients on a gluten-free diet [12, 13]. These findings constitute further evidence that early detection and dietary treatment of coeliac disease is beneficial even in screen-detected patients with mild or atypical symptoms at diagnosis.

There was a significant association between reduced quality of life and the presence of psychiatric co-morbidities in our study patients. This is in accord with some previous findings and there is also evidence that such coeliac patients might benefit from intensified psychological counseling [8, 18, 40‐42]. Consequently, health-care professionals should pay particular attention to this patient group, who may need special support with their dietary treatment [42]. Since in the present study 78% of participants with a psychiatric disorder suffered from depression, the role of other psychiatric disorders needs further investigation. Although not statistically significant, there was a trend suggesting that the presence of certain other co-morbidities, for example neurological disorders, other gastrointestinal diseases or non-coeliac food intolerance are factors predisposing to reduced quality of life in coeliac disease. Further studies are warranted to clarify the significance of these issues.

A major strength of our study was a large study cohort with well-defined coeliac disease diagnoses and clinical data. In addition, there were a substantial number of screen-detected patients and subjects with extraintestinal presentation of coeliac disease. A possible limitation, on the other hand, was that a substantial proportion of the participants were recruited through local or national coeliac disease associations, which might have caused some selection bias. Furthermore, our participants showed excellent adherence to the gluten-free diet, this however being in accord with our earlier findings [12]. Although good adherence is beneficial for the patient, in this study it might have concealed the association between poor adherence and reduced quality of life. As a consequence, results may be different in countries where adherence to a gluten-free diet is lower. Although the threshold value of 1 SD to define increased symptoms and reduced quality of life has also been used in other studies, it is somewhat artificial. The fact that healthy controls were not precisely matched with the study participants was also a limitation.

The majority of participants used oats as a regular part of their diet, and this was not associated with increased gastrointestinal symptoms or reduced quality of life. This is important, since the use of oat-containing products in coeliac disease has hitherto remained controversial [43]. Based on our previous results [44] and the findings here, purified oats could be a regular part of a gluten-free diet. One important issue which should be considered in evaluating gastrointestinal symptoms in coeliac patients is that commercial gluten-free products may have marked qualitative differences, for example in the use of additives and preservatives and the amount of fibre [45].

As a conclusion, we showed that many coeliac disease patients suffer from persistent gastrointestinal symptoms and reduced quality of life despite strict dietary treatment. In particular, long-lasting and severe symptoms before the diagnosis and concomitant thyroid, gastrointestinal and psychiatric co-morbidities were significant risk factors for these ongoing health concerns. The results emphasize the importance of early diagnosis and careful follow-up in coeliac disease.