Psychological morbidity of celiac disease: A review of the literature

Abstract

Background

Celiac disease has been linked to decreased quality of life and certain mood disorders. The effect of the gluten free diet on these psychological aspects of the disease is still unclear.

Objectives

The objective of this article is to review the literature on psychological morbidity of celiac disease.

Methods

We performed a PubMed search for the time period from 1900 until June 1, 2014, to identify papers on psychological aspects of celiac disease looking specifically at quality of life, anxiety, depression and fatigue.

Results

Anxiety, depression and fatigue are common complaints in patients with untreated celiac disease and contribute to lower quality of life. While aspects of these conditions may improve within a few months after starting a gluten-free diet, some patients continue to suffer from significant psychological morbidity. Psychological symptoms may affect the quality of life and the dietary adherence.

Conclusion

Health care professionals need to be aware of the ongoing psychological burden of celiac disease in order to support patients with this disease.

Keywords

Celiac disease anxiety depression fatigue quality of life

Introduction

Celiac disease (CD) is a chronic immune-mediated enteropathy¹ characterized by a large spectrum of symptoms and signs that generally improve with good adherence to a gluten-free diet (GFD).²

In recent years, there has been an increased interest in how celiac patients perceive the impact of their disorder, how this perception relates to the clinical presentation of the disease and how their health is modified by treatment with a GFD. It has been recognized that the aspects of health that should be addressed go beyond the usual biological parameters and extend also to social functioning and psychological issues.³ Mood disorders such as anxiety, depression and fatigue are often linked to CD, before and after diagnosis, and therefore may influence the patient’s quality of life (QoL) and adherence to GFD.

Methods

This work is part of a project initiated by the Oslo group and British Society of Gastroenterology on the clinical management of CD.² We examined the literature on the QoL of celiac patients and some psychological aspects associated with CD (anxiety, depression and fatigue), asking how treatment with a GFD may modify them. A PubMed search identified papers on QoL, anxiety, depression and fatigue published between 1900 and June 1, 2014. Four authors (FZ, GLS, TRC, JCB) carried out the literature searches and the data collection and took the main responsibility for the writing of the paper. DSS and JFL reviewed the paper, giving important feedback.

Results

QoL

Several reports have described the difficulties of living with CD in adults, in particular as regards the impact of this condition on physical, social and emotional factors.^4–23 Unfortunately, interest in the health perception of celiac patients has been affected by the lack of CD-specific QoL instruments allowing measurement of specific aspects of the disorder. Most studies exploring the QoL in CD patients used generic multi-item and multi-dimensional instruments developed for chronic disorders.^24–28 The most widely used generic tools to estimate health-related QoL in CD were the Short Form Health Survey questionnaire²⁶ and the Psychological General Well-being index.²⁸ It is only recently that CD-specific questionnaires have been developed for pediatric^29,30 and adult patients^31,32 and translated into other languages.^33–36 Although screen-detected^37,38 and asymptomatic CD patients³⁹ seem to have a better QoL than symptom-detected patients at the time of diagnosis, the effect of the GFD is still unclear. Mustalahti et al. reported a positive effect of the GFD both in symptomatic and screen-detected patients,³⁷ Johnston et al. suggested the benefits were limited to those presenting with symptomatic disease,³⁸ Vilppula et al.⁴⁰ reported no change of the QoL in screen-detected patients on GFD and finally, Ukkola et al. described that the QoL improved in symptomatic and in screen-detected symptomatic patients but not in screen-detected asymptomatic patients⁴¹ (Figure 1). Interestingly, a time-course assessment of the effect of treatment showed that, in symptomatic patients, the most significant quantitative improvement of most items is seen in the first three months after starting the GFD, with some additional improvement up to one year³⁹ (Figure 1). Compared to biological parameters, including serology, the time course for improvement of QoL measures seems to be earlier and faster.³⁹ Paavola et al., analyzing CD patients on long-term GFD, reported that the QoL was unimpaired in screen-detected celiac patients and lower in symptom-detected patients, when compared to healthy controls.⁴² A recent randomized study showed that asymptomatic CD patients benefited from a GFD for anxiety and better health (based on the visual analog scale), but not for social function, when compared to similar patients following a gluten-containing diet.⁴³ Finally, Roos et al. showed similar psychological well-being in long-treated celiac patients and healthy controls.¹⁶ Poor dietary adherence was associated with a poor QoL^8,10 but whether one causes the other remains unknown, and consequently it is unclear which is the cause and which the effect. A recent long-term longitudinal study suggested that subsequent deterioration in QoL was associated with a lack of dietary adherence.⁴⁴ However, other studies^45,46 reported no differences in QoL scores between patients with full adherence and patients with partial/nonadherence to GFD. Several papers reported lower QoL in women with CD than in celiac men.^9,11–13,18 Finally, Paarlahti et al.⁴⁷ reported that a long duration of symptoms before diagnosis, psychiatric, neurologic or gastrointestinal comorbidities and persistent symptoms were predictors of a reduced QoL.

Figure 1.

Quality of life (QoL) in screen-detected and symptom-detected celiac disease (CD) patients after one year of gluten-free diet. *QoL improved in symptomatic screening-detected patients.

Anxiety

Anxiety has been widely described in CD patients, although a recent meta-analysis⁴⁸ concluded that anxiety is neither more common nor more severe in adults with CD compared to healthy adults. However, large studies are lacking (Table 1). Levels of anxiety appear to increase prior to CD diagnosis, although a diagnosis may be associated with feelings of relief.⁵ Cannings-John et al.⁴⁹ found that celiac patients had an increased number of general practice consultations compared with controls in the five years prior to diagnosis and in particular, three clinical features were independently associated with subsequent diagnosis: depression and/or anxiety, diarrhea and anemia. Addolorato et al. described an increased reactive “state” anxiety in CD patients at diagnosis,^50,51 which decreased after one year of GFD.⁵¹ Conversely, among 441 German adult patients on a GFD, the levels of anxiety and risk of a probable anxiety disorder were found greater than the general population.⁵² Interestingly, anxiety levels were greater in female CD patients compared to male patients, and living alone was associated with a reduced risk of anxiety disorder. The authors speculated that problems with buying and preparing food, plus the associated expense, within a family group may contribute to anxiety. In another study, social phobia, assessed by the Liebowitz Social Anxiety Scale, was found to be significantly greater in 40 celiac patients.⁵³ Among these patients, social phobia levels were similar in newly diagnosed and treated individuals.⁵³ In a study of 68 patients treated for a mean of 10 years, Hallert et al.¹¹ evaluated a nine-item Burden of illness protocol, assessing perceived worries, restrictions and subjective outcome. While the importance of dietary adherence was ranked similarly high by men and women with CD, 10 years after diagnosis women expressed more concerns about the impact of the disease on socializing with friends and having to abstain from important things in life. A recent study⁵⁴ interviewed women with CD and looked at the impact of the condition on everyday living. They expressed a sense of loneliness and invisibility, especially when socializing with others. In another large qualitative study of nearly 6000 Canadians with CD,¹⁷ women reported significantly greater emotional responses to a GFD but, with time, were more accepting of it than men. Frustration and isolation were the most common negative emotions.

Table 1.

Previous literature on depression and anxiety in CD

First author, year of publication	Study population	Outcomes measured	Conclusions
Addolorato, 1996⁵⁰	16 celiac patients 16 IBD 16 Healthy controls	STAI test Ipat Depression Scale Questionnaire	“State” anxiety in celiac patients and IBD patients was increased compared to healthy controls but no increase in personality ‘trait’ anxiety that was present in a similar percentage in all the participants evaluated. Depressive syndrome was more frequent in celiac patients than healthy control group.
Ciacci, 1998⁷¹	92 Celiac patients 100 Healthy controls 48 Patients with CPH	MSDS	Depressive disorder was more frequent in celiac patients than in healthy controls and CPH patients. Age at CD diagnosis, duration of GFD and compliance with diet did not correlate with depression.
Addolorato, 2001⁵¹	35 Celiac patients before (T0) and one year after GFD. 59 Healthy controls	STAI test MSDS	At T0 celiac patients showed high levels of state anxiety and depression compared to controls. After one year of GFD state anxiety decreased significantly but depression did not.
Hallert, 2002¹¹	68 Celiac patients on GFD Matched type-2 DM patients	Nine-item Burden of illness protocol (perceived worries, restrictions and subjective outcome) SF36	Women with CD perceived the health burden to be worse than men and expressed more concern about the impact of socializing with friends.
Carta, 2002⁶⁷	36 Celiac patients 144 Healthy controls	International composite Diagnostic Interview for psychiatric diagnoses based on DSM-IV criteria.	CD patients tended to show higher prevalence of panic disorder and major depressive disorder. Thyroid disease appears to present a significant risk factor for these conditions.
Fera, 2003⁶⁰	100 Celiac patients on GFD 100 Healthy controls 100 DM patients	Professional semi-structured diagnostic interview based on DSM-IV criteria MSDS, STAI test, SF36, IBQ	Depression and anxiety were common features among celiac patients, these disorders tend to improve with the time and they did not depend on diet compliance or demographic variables; Depression and anxiety disorders are significantly higher in both celiac and diabetic patients than healthy controls.
Ciacci, 2003¹³	581 Celiac patients on GFD	MSDS, VAS for the evaluation of anxiety, depression, and positive attitude	Most patients (83.6%) felt “very well” and “well.” Celiac women and patients diagnosed after 20 years of age have better dietary adherence, but more problems in their social life. Anxiety was related to feeling different from the general population and depression to an unsatisfactory sexual life.
Siniscalchi, 2005⁵⁸	71 Celiac patients at diagnosis 59 Celiac patients on GFD 80 Healthy controls	MSDS, CFS questionnaire, FSS, VAS for the evaluation of fatigue	Fatigue and depression symptoms were more frequent in celiac patients than controls. Patients on GFD showed more frequent and severe symptoms of depression than patients at diagnosis.
Ludvigsson, 2007⁷⁰	13,776 Celiac patients 66,815 Healthy controls	Celiac patients with mood disorders and bipolar disorders found through the Swedish National Inpatient Register	CD was associated with an increased risk of subsequent depression (Hazard ratio = 1.8) but it was not associated with subsequent bipolar disorders. Individuals with depression had an increased risk of CD.
Addolorato, 2008⁵³	40 Celiac patients on GFD 50 Healthy controls	Social Phobia assessed by Liebowitz Social Anxiety Scale MSDS	Social phobia and depression were significantly greater in CD patients than controls.
Garud, 2009⁶⁸	600 Celiac patients (mixed) 200 Healthy controls 200 IBS patients	The diagnosis of psychiatric disorders including depression is made from primary care provider notes and gastroenterologist notes.	The prevalence of depression in celiac patients was 17.2% and was similar to those in IBS patients (18.5%) and in controls (16.0%). Among CD patients, depression was more frequent in celiac patients with DM type 1.
Nachman, 2010⁴⁴	53 Celiac patients before (T0) and after one year and four years of GFD	SF36, BDI	At four years, the SF36 and BDI scores showed a significant deterioration compared with one year, but these scores remained significantly better than those at diagnosis. The significant deterioration of scores at four years was related to the lack of adherence to the GFD.
Zingone, 2010⁵⁷	30 Celiac patients at diagnosis 30 Celiac patients on GFD 30 Healthy controls	PSQI, MSDS, STAI test, SF36, VAS for the evaluation of fatigue	Sleep disorders were common in celiac patients at diagnosis and on GFD. Depression, fatigue and anxiety in celiac patients did not improve on GFD. Sleep disorders were directly correlated with the mood disorders.
Häuser, 2010⁵²	441 Celiac patients on GFD 235 IBD patients 441 Healthy controls	HADS	Levels of anxiety were greater in CD and IBD patients than controls. Levels were greater in females than males. Levels of depression did not differ among the three groups.
van Hees, 2013⁶¹	2,265 Adult patients on GFD	HADS, Major Depression Questionnaire, self-report Leiden Index of Depression Sensitivity (short version)	Depression symptoms were present in 39% of CD patients. Long-term GFD (over five years) was associated with a reduced risk of depression. No association between compliance to GFD and depression.

BDI: Beck Depression Inventory; CD: celiac disease; CFS: chronic fatigue syndrome; CPH: chronic persistent hepatitis; FSS: Fatigue Severity Scale; GP: general practice; GFD: gluten-free diet; HADS: Hospital Anxiety and Depression Scale; IBQ: Illness Behavior Questionnaire; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome; MSDS: Modified Zung self-rating Depression Scale; PSQI: Pittsburgh Sleep Quality Index; SF36: Short Form 36 Health Survey; STAI: State & Trait Anxiety Inventory; DM: diabetes mellitus; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.

Depression

Depression has been associated with CD.⁴⁸ Morris et al.⁵⁵ and Hallert et al.⁵⁶ were among the first to describe this association. Though numerous papers have followed the causes of this association and the effect of a GFD on depression, these are still poorly defined (Table 1).

Using the modified Self-Rating Depression Scale, Addolorato et al.⁵¹ described persistent depression after one year of GFD in celiac patients, Zingone et al.⁵⁷ and Siniscalchi et al.⁵⁸ showed that depression was present in CD at diagnosis, but that it persisted or even worsened in patients on a GFD. Nachman et al.,⁴⁴ using the Beck Depression Inventory, showed that depressive symptoms were highly prevalent in untreated CD and there was a significant improvement in psychological symptoms after one year and four years of GFD.⁴⁴ However, the Beck Depression Inventory score at four years showed a significant worsening compared to one year, though CD patients at the four-year visit still had less depression than at CD diagnosis. A low adherence to GFD might be considered either a cause or a consequence of the persistent depression on GFD. This has been suggested in a 2004 study by Addolorato et al., which showed a beneficial effect of psychological support for CD patients on a GFD both in relation to psychological disorders and to improved dietary adherence.⁵⁹ Fera et al.,⁶⁰ in a study of 100 patients treated for eight years, found a high rate of depression, detected by the modified Self-Rating Depression Scale, which tended to improve with time, but which was not correlated with dietary compliance. Similarly, a 2013 cross-sectional study,⁶¹ reporting a self-reported depression prevalence of 39% among 2265 adult CD patients (based on the Major Depression Questionnaire), described that the long-term adherence to the GFD (>5 years) was associated with a reduced risk of depression, but they found no association between insufficient adherence and current depression symptoms. Finally, Häuser et al.⁵² did not find any difference in depression between celiac patients on GFD and the general population. The authors reported no evidence that depression was predicted by diet adherence, years of GFD, presence of associated diseases, or delay in CD diagnosis. Finally, Barratt et al.⁶² described that patients on a GFD, at risk of anxiety and depression according to the Hospital Anxiety Depression Scale, reported more symptoms in response to occasional dietary gluten exposure.

Mechanisms explaining psychological morbidities

As Table 2 shows, a number of mechanisms may explain the relationship between CD and psychological morbidities such as anxiety and depression, either before or after CD diagnosis. Before diagnosis, they may be a consequence of the disease symptoms with a decreased sensation of general well-being.⁶³ Equally, they may be due to cerebral hypoperfusion in some brain regions,⁶⁴ be a consequence of vitamin deficiency due to malabsorption⁶⁵ or of hyperhomocysteinemia, which might, by damaging the blood-brain barrier, expose neuronal tissue to neuro-irritative metabolites.⁶⁶ On a GFD, they may be particularly sustained by dietary restrictions and by compromised daily social relationships.²¹ Independently of GFD, psychological morbidities in CD may also be secondary to CD associated with autoimmune diseases. For example, Carta et al. in 2002⁶⁷ showed that the association of CD with thyroid disease can represent a significant risk factor for depression and panic disorders. Some years later, Garud et al.⁶⁸ described a similar risk of depression in CD when compared with the general population but a markedly elevated risk of depression in patients both with CD and type I diabetes. A possible explanation of this increased risk may be that the cytokines produced by immune reactions may exercise an effect on the brain circuits responsible for mood regulation.⁶⁹ However, a large Swedish population-based study⁷⁰ based on 13776 CD patients found that CD patients were at an 80% increased risk of depression compared to controls and the adjustment for type 1 diabetes or thyroid disease did not affect the risk estimates.⁷⁰ Finally, these psychological morbidities could also be a consequence of a chronic condition: in fact while Ciacci et al. found a higher prevalence of symptoms of depression in CD patients than in patients with chronic hepatitis,⁷¹ others have found no difference between depression in CD compared to patients with irritable bowel syndrome (IBS),⁶⁸ and depression and anxiety compared to patients with type 2 diabetes.⁶⁰ Finally, Häuser et al.⁵² described levels of anxiety greater in CD and in patients with inflammatory bowel diseases compared to controls and similar levels of depression among the three groups.

Table 2.

Mechanisms potentially leading to psychological morbidity in celiac disease

Pre-diagnosis	Post-diagnosis
Reduced well-being⁶³	Dietary restrictions and compromised daily social relationships²¹
Cerebral hypoperfusion⁶⁴	Chronic conditions status^52,60,68
Vitamin deficiency⁶⁵	Associated autoimmune diseases^67,68
Hyperhomocysteinemia⁶⁶
Associated autoimmune diseases^67,68

Depression and anxiety may be associated with other factors including an unsatisfactory sexual life,¹³ fatigue⁵⁸ and poor quality of sleep.⁵⁷ Furthermore, functional disorders, such as IBS^72–74 and functional dyspepsia^74,75 are frequently diagnosed in CD patients at diagnosis and in those on a long-term GFD. Since these disorders are also associated with reduced QoL and increase the likelihood of anxiety and depression in CD,^76,77 treating these comorbidities may improve QOL and mood disorders in CD.⁷³

CD has been linked to a number of neurological disorders: ataxia,⁷⁸ neuropathy,⁷⁹ epilepsy,⁸⁰ and headache⁸¹ while the evidence in multiple sclerosis has been mixed.^79,82 Several of the above neurological disorders have been linked to poor QoL,^83–85 and we cannot rule out that psychological dimensions of neurological comorbidity have thereby influenced QoL in CD patients. Neurological and psychological morbidities in CD patients might be caused by the mechanisms reported above, such as vitamin deficiency and hyperhomocysteinemia, as well as by the presence of antineuronal antibodies⁸⁶ and brain dysfunctions.⁸⁷ For example, a similar gray matter loss described in particular in the gyrus rectus and anterior cingulate gyrus of CD patients with neurological disturbances⁸⁷ has also been reported in individuals with depression.^88,89

Fatigue

There is now good evidence to show not only that fatigue can be a symptom of CD, but also that it is a common clinical presentation.^90–93 Serological screening for CD is now recommended in the workup of chronic fatigue.⁹⁴ Case finding studies suggest a CD prevalence of about 3% among those presenting with chronic fatigue, i.e. similar to that in patients with IBS.⁹² Less is known about the prevalence of fatigue among those already on a GFD, or whether treatment of CD with a GFD successfully treats this symptom. In the last decade a small number of studies have more directly addressed these issues. Siniscalchi et al. in 2005 demonstrated that celiac patients both at diagnosis and when on a GFD had higher levels of fatigue than healthy controls using a variety of validated scales.⁵⁸ Perhaps more surprisingly, fatigue was not significantly different between newly diagnosed celiac patients and those on an established GFD. The same researchers from Naples have since shown that both treated and untreated celiac patients experience a worse quality of sleep than healthy volunteers⁵⁷ perhaps offering an explanation of the mechanisms behind this condition. Again, treated celiac patients did not show significantly different characteristics compared with their untreated counterparts. More recently, a large questionnaire study of 5912 Canadian celiac patients has suggested that “extreme weakness/tiredness” is reported by patients to improve over a prolonged period on GFD, such that of those on GFD for more than five years 72.4% reported this symptom had recovered.⁹⁵ Interpretation of these findings is made more difficult by the fact that data originate from cross-sectional studies, rather than from either randomized controlled trials of the effect of GFD, or cohort studies to permit examination of the alteration in state within individuals after establishment of a diet. It is therefore unwise to conclude too firmly that GFD either does or does not alleviate fatigue in CD from the available evidence. One other potentially relevant finding is the suggestion that dietary supplementation with L-carnitine may treat fatigue in CD.⁹⁶ Since carnitine is absorbed in the small intestine,⁹⁷ it is tempting to assume that resolution of malabsorption should facilitate the intestinal uptake of carnitine. However, the range of gastroenterological and non-gastrointestinal conditions in which similar effects have been suggested indicates that mechanisms other than the correction of a deficiency may be operating.^98,99

Summary

Our search of the available literature suggests that CD has a considerable psychological impact. Some elements of this may relate to the disease and its biochemical effects, but other aspects relate to the patient’s subjective perception of the disorder and of the GFD used to treat it. The treatment of CD results in a significant improvement in QoL for symptomatic patients, but patients with subclinical CD often report no such effect. However, a proportion of subclinical patients may report improvement in QoL parameters after commencing treatment. Overall, levels of anxiety and depression are greater in patients with CD (Table 1). However, the causes of this may vary at different stages (Table 2). Prior to CD diagnosis, patients may express concerns about unexplained symptoms and may feel frustrated about repeated consultations that offer no adequate explanation of their problems. At the time of diagnosis, there may be concerns about investigations and a diagnosis of a long-term condition, although this may be accompanied by a feeling of relief that a diagnosis has finally been made. While some psychological problems may lessen with time as knowledge of the condition improves and perhaps biochemical abnormalities are corrected, it appears that many patients have ongoing concerns about coping with the diet and do not adhere to it, particularly when going out and in social interaction. Fatigue is sometimes the unique symptom at CD presentation. Conversely, 3% of patients with chronic fatigue may be found to have CD. The available studies have not been able to show a consistent positive effect of the GFD in diminishing perception of fatigue.

Conclusion

The literature on the effect of treatment in the outcome of depression, anxiety, fatigue and QoL in CD is not consistent. However, it is important to consider that ongoing problems with anxiety and depression in particular may affect dietary adherence and QoL. Thus, health care professionals need to be aware of the ongoing psychological burden of CD in order to support their patients. The lack of clear evidence of improved QoL in asymptomatic CD after treatment makes mass screening, where a majority of patients may be subclinical or asymptomatic, controversial if the aim of screening is to improve QoL. Further studies are required to better understand this specific aspect.

Clinical implications

Celiac disease (CD) has a considerable psychological impact.

Biochemical effects and the patient’s subjective perception of the disorder and of the gluten-free diet (GFD) may be causes of the psychological morbidities.

GFD improves quality of life (QoL) in symptomatic patients, but not always in asymptomatic patients.

Anxiety and depression may affect dietary adherence and QoL.

Fatigue is sometimes the unique symptom at CD presentation.

Health care professionals need to support CD patients on GFD.

There is no evidence to support mass screening as the GFD fails to improve the QoL in asymptomatic, screen-detected CD patients.

Footnotes

Funding

JFL was supported by grants from The Swedish Society of Medicine and the Swedish Research Council – Medicine (522-2A09-195). TC derives his salary from the University of Nottingham and the Nottingham University Hospitals NHS trust.

Conflict of interest

TC has received grant support from Coeliac UK: Crohn’s and Colitis UK. DSS has received an educational grant from Dr Schär (a gluten-free food manufacturer) to undertake an investigator-led research study on gluten sensitivity. He also has received an educational grant both from Biocard and Simtomax to undertake an investigator-led research study on point-of-care tests.

References

Ludvigsson

Leffler

Bai

. The Oslo definitions for coeliac disease and related terms. Gut 2013; 62: 43–52.

Ludvigsson

Bai

Biagi

. Diagnosis and management of adult coeliac disease: Guidelines from the British Society of Gastroenterology. Gut 2014; 63: 1210–1228.

Troncone

Ivarsson

Szajewska

. Review article: Future research on coeliac disease—a position report from the European multistakeholder platform on coeliac disease (CDEUSSA). Aliment Pharmacol Ther 2008; 27: 1030–1043.

Hallert

Lohiniemi

. Quality of life of celiac patients living on a gluten-free diet. Nutrition 1999; 15: 795–795.

Ciacci

Iavarone

Siniscalchi

. Psychological dimensions of celiac disease: Toward an integrated approach. Dig Dis Sci 2002; 47: 2082–2087.

Lee

Newman

. Celiac diet: Its impact on quality of life. J Am Diet Assoc 2003; 103: 1533–1535.

De Rosa

Troncone

Vacca

. Characteristics and quality of illness behavior in celiac disease. Psychosomatics 2004; 45: 336–342.

Häuser

Stallmach

Caspary

. Predictors of reduced health-related quality of life in adults with coeliac disease. Aliment Pharmacol Ther 2007; 25: 569–578.

Hallert

Grännö

Grant

. Quality of life of adult coeliac patients treated for 10 years. Scand J Gastroenterol 1998; 33: 933–938.

10.

Usai

Minerba

Marini

. Case control study on health-related quality of life in adult coeliac disease. Dig Liver Dis 2002; 34: 547–552.

11.

Hallert

Grännö

Hulten

. Living with coeliac disease: Controlled study of the burden of illness. Scand J Gastroenterol 2002; 37: 39–42.

12.

Hallert

Sandlund

Broqvist

. Perceptions of health-related quality of life of men and women living with coeliac disease. Scand J Caring Sci 2003; 17: 301–307.

13.

Ciacci

D’Agate

De Rosa

. Self-rated quality of life in celiac disease. Dig Dis Sci 2003; 48: 2216–2220.

14.

Green

PHR

Stavropoulos

Panagi

. Characteristics of adult celiac disease in the USA: Results of a national survey. Am J Gastroenterol 2001; 96: 126–131.

15.

Häuser

Gold

Stein

. Health-related quality of life in adult coeliac disease in Germany: Results of a national survey. Eur J Gastroenterol Hepatol 2006; 18: 747–754.

16.

Roos

Kärner

Hallert

. Psychological well-being of adult coeliac patients treated for 10 years. Dig Liver Dis 2006; 38: 177–180.

17.

Zarkadas

Dubois

MacIsaac

. Living with coeliac disease and a gluten-free diet: A Canadian perspective. J Hum Nutr Diet 2013; 26: 10–23.

18.

Jacobsson

Hallert

Milberg

. Coeliac disease—women’s experiences in everyday life. J Clin Nurs 2012; 21: 3442–3450.

19.

Byström

Hollén

Fälth-Magnusson

. Health-related quality of life in children and adolescents with celiac disease: From the perspectives of children and parents. Gastroenterol Res Pract 2012; 2012: 986475–986475.

20.

Ford

Howard

Oyebode

. Psychosocial aspects of coeliac disease: A cross-sectional survey of a UK population. Br J Health Psychol 2012; 17: 743–757.

21.

Lee

Diamond

. Living with coeliac disease: Survey results from the USA. J Hum Nutr Diet 2012; 25: 233–238.

22.

Roos

Hellström

Hallert

. Everyday life for women with celiac disease. Gastroenterol Nurs 2013; 36: 266–273.

23.

Sainsbury

Mullan

Sharpe

. Reduced quality of life in coeliac disease is more strongly associated with depression than gastrointestinal symptoms. J Psychosom Res 2013; 75: 135–141.

24.

Aaronson

Acquadro

Alonso

. International quality of life assessment (IQOLA) project. Qual Life Res 1992; 1: 349–351.

25.

Borgaonkar

Irvine

. Quality of life measurement in gastrointestinal and liver disorders. Gut 2000; 47: 444–454.

26.

Riddle

Lee

Stratford

. Use of SF-36 and SF-12 health status measures: A quantitative comparison for groups versus individual patients. Med Care 2001; 39: 867–878.

27.

Eypasch

Williams

Wood-Dauphinee

. Gastrointestinal Quality of Life Index: Development, validation and application of a new instrument. Br J Surg 2005; 82: 216–222.

28.

Rasmussen

Norholm

Bech

. The internal and external validity of the Psychological General Well-Being Schedule (PGWB). Quality of Life News Letter 1999; 22: 7–7.

29.

van Doorn

Winkler

LMF

Zwinderman

. CDDUX: A disease-specific health-related quality-of-life questionnaire for children with celiac disease. J Pediatr Gastroenterol Nutr 2008; 47: 147–152.

30.

Jordan

Magrini

. Development and validation of a celiac disease quality of life instrument for North American children. J Pediatr Gastroenterol Nutr 2013; 57: 477–486.

31.

Häuser

Gold

Stallmach

. Development and validation of the Celiac Disease Questionnaire (CDQ), a disease-specific health-related quality of life measure for adult patients with celiac disease. J Clin Gastroenterol 2007; 41: 157–166.

32.

Dorn

Hernandez

Minaya

. The development and validation of a new coeliac disease quality of life survey (CD-QOL). Aliment Pharmacol Ther 2010; 31: 666–675.

33.

Pouchot

Despujol

Malamut

. Validation of a French version of the Quality of Life “Celiac Disease Questionnaire”. PloS One 2014; 9: e96346–e96346.

34.

Zingone

Iavarone

Tortora

. The Italian translation of the Celiac Disease-specific Quality of Life Scale in celiac patients on gluten free diet. Dig Liver Dis 2013; 45: 115–118.

35.

Casellas

Rodrigo

Molina-Infante

. Transcultural adaptation and validation of the Celiac Disease Quality of Life (CD-QOL) survey, a specific questionnaire to measure quality of life in patients with celiac disease. Rev Esp Enferm Dig 2013; 2013: 585–593.

36.

Marchese

Klersy

Biagi

. Quality of life in coeliac patients: Italian validation of a coeliac questionnaire. Eur J Intern Med 2013; 24: 87–91.

37.

Mustalahti

Lohiniemi

Collin

. Gluten-free diet and quality of life in patients with screen-detected celiac disease. Eff Clin Pract 2002; 5: 105–113.

38.

Johnston

Rodgers

Watson

RGP

. Quality of life in screen-detected and typical coeliac disease and the effect of excluding dietary gluten. Eur J Gastroenterol Hepatol 2004; 16: 1281–1281.

39.

Nachman

Maurino

Vázquez

. Quality of life in celiac disease patients: Prospective analysis on the importance of clinical severity at diagnosis and the impact of treatment. Dig Liver Dis 2009; 41: 15–25.

40.

Vilppula

Kaukinen

Luostarinen

. Clinical benefit of gluten-free diet in screen-detected older celiac disease patients. BMC Gastroenterol 2011; 11: 136–136.

41.

Ukkola

Mäki

Kurppa

. Diet improves perception of health and well-being in symptomatic, but not asymptomatic, patients with celiac disease. Clin Gastroenterol Hepatol 2011; 9: 118–123.

42.

Paavola

Kurppa

Ukkola

. Gastrointestinal symptoms and quality of life in screen-detected celiac disease. Dig Liver Dis 2012; 44: 814–818.

43.

Kurppa

Paavola

Collin

. Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology 2014; 147: 610–617.e1.

44.

Nachman

del Campo

González

. Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance. Dig Liver Dis 2010; 42: 685–691.

45.

Barratt

Leeds

Sanders

. Quality of life in coeliac disease is determined by perceived degree of difficulty adhering to a gluten-free diet, not the level of dietary adherence ultimately achieved. J Gastrointestin Liver Dis 2011; 20: 241–245.

46.

Hopman

Koopman

Wit

. Dietary compliance and health-related quality of life in patients with coeliac disease. Eur J Gastroenterol Hepatol 2009; 21: 1056–1056.

47.

Paarlahti

Kurppa

Ukkola

. Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: A large cross-sectional study. BMC Gastroenterol 2013; 13: 75–75.

48.

Smith

Gerdes

. Meta-analysis on anxiety and depression in adult celiac disease. Acta Psychiatr Scand 2012; 125: 183–193.

49.

Cannings-John

Butler

Prout

. A case-control study of presentations in general practice before diagnosis of coeliac disease. British J Gen Pract 2007; 57: 636–642.

50.

Addolorato

Stefanini

Capristo

. Anxiety and depression in adult untreated celiac subjects and in patients affected by inflammatory bowel disease: A personality “trait” or a reactive illness? Hepatogastroenterology 1996; 43: 1513–1513.

51.

Addolorato

Capristo

Ghittoni

. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: A longitudinal study. Scand J Gastroenterol 2001; 36: 502–506.

52.

Häuser

Janke

Klump

. Anxiety and depression in adult patients with celiac disease on a gluten-free diet. World J Gastroenterol 2010; 16: 2780–2780.

53.

Addolorato

Mirijello

D’Angelo

. Social phobia in coeliac disease. Scand J Gastroenterol 2008; 43: 410–415.

54.

Taylor

Dickson-Swift

Anderson

. Coeliac disease: The path to diagnosis and the reality of living with the disease. J Hum Nutr Diet 2013; 26: 340–348.

55.

Morris JS, Ajdukiewicz A and Read A. Neurological disorders and adult coeliac disease. Gut 1970; 11: 549–554.

56.

Hallert C, Åstrøm J and Sedvall G. Psychic disturbances in adult coeliac disease. Scand J Gastroenterol 1982; 17: 25–28.

57.

Zingone F, Siniscalchi M, Capone P, et al. The quality of sleep in patients with coeliac disease. Aliment Pharmacol Ther 2010; 32: 1031–1036.

58.

Siniscalchi M, Iovino P, Tortora R, et al. Fatigue in adult coeliac disease. Aliment Pharmacol Ther 2005; 22: 489–494.

59.

Addolorato G, De Lorenzi G, Abenavoli L, et al. Psychological support counselling improves gluten-free diet compliance in coeliac patients with affective disorders. Aliment Pharmacol Ther 2004; 20: 777–782.

60.

Fera T, Cascio B, Angelini G, et al. Affective disorders and quality of life in adult coeliac disease patients on a gluten-free diet. Eur J Gastroenterol Hepatol 2003; 15: 1287–1292.

61.

Van Hees NJ, Van der Does W and Giltay EJ. Coeliac disease, diet adherence and depressive symptoms. J Psychosom Res 2013; 74: 155–160.

62.

63.

Kurppa K, Collin P, Mäki M, et al. Celiac disease and health-related quality of life. Expert Rev Gastroenterol Hepatol 2011; 5: 83–90.

64.

Addolorato G, Giuda DD, Rossi GD, et al. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004; 116: 312–317.

65.

Hallert C, Svensson M and Tholstrup J, et al. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther 2009; 29: 811–816.

66.

Ferretti A, Parisi P and Villa MP. The role of hyperhomocysteinemia in neurological features associated with coeliac disease. Med Hypotheses 2013; 81: 524–531.

67.

Carta MG, Hardoy MC, Boi MF, et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res 2002; 53: 789–793.

68.

Garud S, Leffler D, Dennis M, et al. Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States. Aliment Pharmacol Ther 2009; 29: 898–905.

69.

Tsigos C and Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002; 53: 865–871.

70.

Ludvigsson JF, Reutfors J, Ösby U, et al. Coeliac disease and risk of mood disorders: a general population-based cohort study. J Affect Disord 2007; 99: 117–126.

71.

Ciacci C, Iavarone A, Mazzacca G, et al. Depressive symptoms in adult coeliac disease. Scand J Gastroenterol 1998; 33: 247–250.

72.

Sainsbury

Sanders

Ford

. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: A meta-analysis. Clin Gastroenterol Hepatol 2013; 11: 359–365.

73.

Barratt

Leeds

Robinson

. Reflux and irritable bowel syndrome are negative predictors of quality of life in coeliac disease and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2011; 23: 159–159.

74.

Turco

Boccia

Miele

. The association of coeliac disease in childhood with functional gastrointestinal disorders: A prospective study in patients fulfilling Rome III criteria. Aliment Pharmacol Ther 2011; 34: 783–789.

75.

Giangreco

D’agate

Barbera

. Prevalence of celiac disease in adult patients with refractory functional dyspepsia: Value of routine duodenal biopsy. World J Gastroenterol 2008; 14: 6948–6948.

76.

Mönnikes

. Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol 2011; 45: S98–S101.

77.

Filipović

Randjelovic

Ille

. Anxiety, personality traits and quality of life in functional dyspepsia-suffering patients. Eur J Intern Med 2013; 24: 83–86.

78.

Hadjivassiliou

Grünewald

Sharrack

. Gluten ataxia in perspective: Epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126: 685–691.

79.

Ludvigsson

Olsson

Ekbom

. A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases. Aliment Pharmacol Ther 2007; 25: 1317–1327.

80.

Ludvigsson

Zingone

Tomson

. Increased risk of epilepsy in biopsy-verified celiac disease: A population-based cohort study. Neurology 2012; 78: 1401–1407.

81.

Hadjivassiliou

Grünewald

Lawden

. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001; 56: 385–388.

82.

Rodrigo

Hernández-Lahoz

Fuentes

. Prevalence of celiac disease in multiple sclerosis. BMC Neurol 2011; 11: 31–31.

83.

Ferro MA. Risk factors for health-related quality of life in children with epilepsy: A meta-analysis. Epilepsia. Epub ahead of print 19 September 2014.

84.

Kim

Park

. The role of headache chronicity among predictors contributing to quality of life in patients with migraine: A hospital-based study. J Headache Pain 2014; 15: 68–68.

85.

Calvert

Pall

Hoppitt

. Health-related quality of life and supportive care in patients with rare long-term neurological conditions. Qual Life Res 2013; 22: 1231–1238.

86.

Briani

Zara

Alaedini

. Neurological complications of celiac disease and autoimmune mechanisms: A prospective study. J Neuroimmunol 2008; 195: 171–175.

87.

Currie

Hadjivassiliou

Clark

. Should we be ‘nervous’ about coeliac disease? Brain abnormalities in patients with coeliac disease referred for neurological opinion. J Neurol Neurosurg Psychiatry 2012; 83: 1216–1221.

88.

Ballmaier

Toga

Blanton

. Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: An MRI-based parcellation of the prefrontal cortex. Am J Psychiatry 2004; 161: 99–108.

89.

Bremner

Vythilingam

Vermetten

. Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 2002; 51: 273–279.

90.

Di Lazzaro

Pilato

Batocchi

. Tired legs—a gut diagnosis. Lancet 2010; 376: 1798–1798.

91.

Carnevale

Filabozzi

Cela

. Tiredness: A feature of coeliac disease. Age Ageing 2000; 29: 462–463.

92.

Sanders

Patel

Stephenson

. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003; 15: 407–413.

93.

Skowera

Peakman

Cleare

. High prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome. J Clin Pathol 2001; 54: 335–336.

94.

National Collaborating Centre for Primary Care. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy) in adults and children, London: National Institute for Health and Clinical Excellence, 2007.

95.

Pulido

Zarkadas

Dubois

. Clinical features and symptom recovery on a gluten-free diet in Canadian adults with celiac disease. Can J Gastroenterol 2013; 27: 449–453.

96.

Ciacci

Peluso

Iannoni

. L-Carnitine in the treatment of fatigue in adult celiac disease patients: A pilot study. Dig Liver Dis 2007; 39: 922–928.

97.

Lloyd

Gudjonsson

. The effect of enteral carnitine administration in humans. Am J Clin Nutr 1992; 55: 838–845.

98.

Anty

Marjoux

Bekri

. Plasma carnitine is associated with fatigue in chronic hepatitis C but not in the irritable bowel syndrome. Aliment Pharmacol Ther 2011; 33: 961–968.

99.

Pistone

Marino

Leotta

. Levocarnitine administration in elderly subjects with rapid muscle fatigue: Effect on body composition, lipid profile and fatigue. Drugs Aging 2003; 20: 761–767.