- Email: [email protected]
Increased suicide risk in coeliac disease—A Swedish nationwide cohort study
Digestive and Liver Disease 43 (2011) 616–622
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Increased suicide risk in coeliac disease—A Swedish nationwide cohort study夽 Jonas F. Ludvigsson a,b,∗ , Carl Sellgren c , Bo Runeson d , Niklas Långström c,e , Paul Lichtenstein c a
Department of Paediatrics, Örebro University Hospital, Sweden Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden d Department of Clinical Neuroscience, Karolinska Institutet, Sweden e Centre for Violence Prevention, Karolinska Institutet, Sweden b
a r t i c l e
i n f o
Article history: Received 25 November 2010 Accepted 4 February 2011 Available online 17 March 2011 Keywords: Autoimmunity Coeliac Inflammation Suicide
a b s t r a c t Background and aim: Individuals with coeliac disease have increased risk of depression and death from external causes, but conclusive studies on death from suicide are missing. We examined the risk of suicide in coeliac disease and amongst individuals where the small intestinal biopsy showed no villous atrophy. Methods: We collected biopsy data from all 28 clinical pathology departments in Sweden for individuals diagnosed during 1969–2007 with coeliac disease (Marsh 3: villous atrophy; n = 29,083 unique individuals), inflammation without villous atrophy (Marsh 1–2; n = 13,263) or positive coeliac disease serology but normal mucosa (Marsh 0, n = 3719). Through Cox regression we calculated Hazard ratios for suicide as recorded in the Swedish Cause of Death Register. Results: The risk for suicide was higher in patients with coeliac disease compared to general population controls (HR = 1.55; 95%CI = 1.15–2.10; based on 54 completed suicides). Whilst suicide was also more common amongst individuals with inflammation (HR = 1.96; 95%CI = 1.39–2.77), no such increase was seen amongst individuals with a normal mucosa but positive coeliac disease serology (HR = 1.06; 95%CI = 0.37–3.02). Conclusions: We found a moderately increased risk of suicide amongst patients with coeliac disease. This merits increased attention amongst physicians treating these patients. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Coeliac disease (CD) is an immune-mediated disorder triggered by exposure to gluten. CD occurs in some 1/100 individuals, and is associated with a number of other somatic disorders including endocrine disease [1], sepsis [2] and osteoporosis [3]; but there are also several studies suggesting a positive association between CD and depression [4–10]. The mechanism behind the association between CD and depression may include conditions of the central nervous system [11], somatic comorbidity [1–3], poor quality of life [12], and economic restraints caused by health care and adherence to a gluten-free diet [13] – or a combination of these. Some data also indicate that the association with depression does not abate with a
夽 Disclaimer: None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Guarantor: JFL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. ∗ Corresponding author at: Department of Paediatrics, Örebro University Hospital, Sweden. Tel.: +46 (0) 19 6021000; fax: +46 (0) 19 187915. E-mail address: [email protected] (J.F. Ludvigsson).
gluten-free diet [4,7]. Since CD has been associated with psychiatric disorders, it is possible that patients with CD are at increased risk for suicide. In a recent paper, we found a 39% increased risk of overall death in CD [14]; most individuals died from cardiovascular disorder, malignancy and respiratory disease. However, other causes of death were also more common in individuals with CD (Hazard ratio, HR = 1.65; 95%CI = 1.51–1.81)[14]. We know of no large-scale studies on CD and suicide. An earlier Swedish study indicated an increased risk of death from external causes in CD [15], but that study was restricted to inpatients, and did not specifically examine the risk of suicide. A British study suggested an increased risk of death from accidents, suicides and violence in children, but not in adults, with CD [16]. Since the association between CD and suicide remains uncertain, we conducted a retrospective cohort study to compare the risk of suicide amongst 29,000 individuals in Sweden with biopsyverified CD (with villous atrophy, VA) during 1969–2007 with that amongst general population controls. For comparative reasons, we also estimated the risk of suicide in individuals with small intestinal inflammation but without VA, and those with normal mucosa but positive CD serology.
1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.02.009
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
2. Methods By using the unique Personal Identity Number (PIN) [17], we linked nationwide data on small intestine histopathology with data on suicide from the Swedish National Cause of Death Registry. Additional data were obtained from the National Hospital Discharge and Education Registries. The study was approved by the Research Ethics Committee of Karolinska Institutet. 2.1. Collection of biopsy data Between October 2006 and February 2008, we contacted all clinical pathology departments in Sweden (n = 28) to obtain data on duodenal/jejunal biopsy reports [18]. Local IT technicians performed searches, and delivered data on (a) arrival date of the biopsies, (b) PIN, (c) morphology according to Swedish SnoMed classification codes [18] and (d) topography (duodenum or jejunum). For the purpose of this paper, SnoMed codes were translated into corresponding Marsh stages (see Appendix). Data searches were restricted to computerised records; hence, the majority of patients in this study were biopsied after 1990 (Table 1). Small intestinal morphology was graded into VA (Marsh stage 3, and equal to CD), inflammation without VA (Marsh 1–2) and normal mucosa (Marsh 0). A detailed list of relevant morphology codes has been published elsewhere [18] (see also Appendix). We based the CD diagnosis solely on small intestinal morphology; positive CD serology was not required for the diagnosis. For a diagnosis of inflammation, we required a SnoMed code corresponding to duodenal/jejunal inflammation [18] but no biopsy-verified VA. In the most commonly used Swedish histopathology classification (“KVAST” – the Swedish committee on quality and standardisation), inflammation is equivalent to intraepithelial lymphocytosis. The Swedish classification does not distinguish between Marsh 1 and 2. In this study, we used the same dataset as in a recent paper on overall mortality in CD [14]. After the exclusion of duplicates and biopsies with data irregularities (e.g. a biopsy seemingly performed before birth or after the death of an individual), we had data from 351,403 biopsy reports in 287,586 unique individuals (CD: 29,148; inflammation: 13,446 and normal biopsy: 244,992). Individuals with normal mucosa but positive CD serology were identified through linkage of biopsy report data (in a subset of individuals with normal mucosa, n = 121,952) with positive CD serology data from eight university hospitals in Sweden. Although these hospitals care for 49% of the Swedish population [19], living in both urban and rural areas, data on normal mucosa but positive CD serology were hence regional, not nationwide. Through this linkage, we obtained data on date of test, type of test [antigliadin, endomysial (EMA), tissue transglutaminase (TTG)], antibody levels, IgA/IgG ratios and age-specific reference values at the time of testing for all individuals with normal mucosa [20]. In this study, we defined “positive CD serology” as positive when obtained up to 180 days before a normal biopsy, and until 30 days after such biopsy [20] in individuals who never had a biopsy with VA or inflammation; 3736 individuals fulfilled these criteria [20]. Hence, individuals with more than one biopsy were defined according to the biopsy with the highest Marsh grade (most severe histopathology). Data on each individual undergoing biopsy (total n = 46,330) were sent for matching by the government agency Statistics Sweden. Additional exclusions are presented in Fig. 1. 2.2. Reference individuals Each individual undergoing biopsy was matched with up to five reference individuals by age, sex, county and calendar year
617
through the Total Population Register [21]. All Swedish residents who had had no recorded biopsy with CD, inflammation or normal mucosa but positive CD serology when their matched index individual underwent biopsy were eligible as reference individuals. In total, Statistics Sweden identified 229,800 reference individuals. We then excluded individuals with data irregularities or since they could not be matched with any individual undergoing biopsy (Fig. 1). In all, this study was based on 29,083 individuals with CD, 13,263 with inflammation, 3719 with normal mucosa but positive CD serology and 228,350 general population reference individuals. 2.3. Outcome measure We used ICD E-codes to define suicide in the longitudinal Cause of Death Register (operative from 1953): ICD-8 and ICD-9: E-codes 950-959 and 980-989; ICD-10: X60-X85 and Y10-34. We included both certain and uncertain suicides since the exclusion of uncertain suicides may lead to an underestimation of true suicides [22]. In 1995, the National Board of Health and Welfare received death certificates on 99.7% of all deaths, suggesting excellent coverage. 2.4. Other covariates Through relevant ICD codes in the Hospital Discharge Register we identified study participants with type 1 diabetes, autoimmune thyroid disease, depressive disorders, anxiety or phobic disorders as well as any psychiatric disorder (see Appendix). Education: To adjust for education, we used seven predefined levels, ranging from not completed 9-year compulsory school to PhD-degree, obtained from the Education Register. 2.5. Statistical analyses Cox regression modelling provided HRs for death from suicide. The Cox regression was internally stratified; the index individual was only compared with his/her reference individuals within the same stratum; and then a summary risk estimate was calculated. The proportional hazards assumption was tested through plotting logminuslog curves. Follow-up began on date of first positive biopsy (CD, inflammation or normal mucosa in an individual with positive CD serology at time of biopsy) and corresponding date in matched reference individuals. Follow-up ended with death from suicide, death from other cause, emigration or on December 31st 2007, whichever happened first. In reference individuals, follow-up could also end if the individual had a biopsy with CD or inflammation, or normal mucosa but positive CD serology after matching had occurred. In a priori subanalyses, we examined the risk of suicide by follow-up period (<1 year, 1–4.99 and ≥5 years), sex, age (0–19, 20–39, 40–59 and ≥60 years at first biopsy), and calendar period of first biopsy (–1989, 1990–1999 and 2000–). We calculated incidence rates as number of suicides divided by person-years at risk. In separate analyses, we adjusted for type 1 diabetes and autoimmune thyroid disease as well as education. Both type 1 diabetes and autoimmune thyroid disease could influence hospital admission patterns amongst individuals with CD and potentially also the risk of suicide. Education or socioeconomic status may also influence health care use (and ascertainment of CD) [23], and risk of suicide [24]. To estimate the influence of psychiatric disorder on the risk of suicide in patients with CD, we adjusted for psychiatric disorder in two analyses. Firstly, we adjusted for an inpatient diagnosis of a depressive or anxiety disorder at some stage of life from 1973 and onwards. Secondly, we adjusted for any lifetime psychiatric disorder.
618
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
Table 1 Characteristics of study participants in a Swedish nationwide retrospective cohort study of suicide in coeliac disease. Characteristic
Coeliac disease (N = 29,083) Inflammation (N = 13,263) Normal mucosa but positive CD serologya (N = 3,719)
Female sex (%) Male sex (%) Age at study entry, years (median; range) Age 0–19 (%) Age 20–39 (%) Age 40–59 (%) Age ≥60 (%) Entry year (median; range) Calendar year for diagnosis –1989 (%) 1990–1999 (%) 2000– (%) Follow-up, years (median; range) Follow-up, years (mean; SD) Diagnosis of type 1 diabetes (%) Lifetime diagnosis of depressive or anxiety disorder (%) Lifetime diagnosis of any psychiatric disorder (%)
17,997 (61.9) 11,086 (38.1) 40; 1–100 11,798 (40.6) 5,309 (18.3) 6,473 (22.3) 5,503 (18.9) 1998; 1969–2007
7,469 (56.3) 5,764 (43.7) 59; 2–104 1,224 (9.2) 3,529 (26.6) 4,133 (31.2) 4,377 (33.0) 1999; 1970–2007
2,310 (62.1) 1,409 (37.9) 43; 2–97 941 (25.3) 1,150 (30.9) 1,064 (28.6) 564 (15.2) 2001; 1990–2007
4,105 (14.1) 12,059 (41.5) 12,919 (44.4) 8.1; 0–38.5 9.4; 6.4 1,319 (4.5) 1,019 (3.5) 2,240 (7.7)
1,961 (14.8) 5,164 (38.9) 6,138 (46.3) 6.6; 0–32.7 8.0; 6.5 440 (3.3) 849 (6.4) 1,633 (12.3)
0 (0) 1,387 (37.2) 2,332 (62.7) 5.9; 0–17.8 6.7; 4.3 111 (3.0) 151 (4.1) 337 (9.1)
Note: CD (coeliac disease) serology included IgA/IgG gliadin, endomysial and tissue transglutaminase antibodies.
2.6. Post-hoc analyses In a post-hoc analysis we examined the risk of suicide in CD vs. inflammation and normal mucosa but positive CD serology adjusting for sex, age at biopsy and calendar year at biopsy. We used SPSS 16.0 to perform all analyses. HRs with 95%CIs not including 1 were regarded as statistically significant. 3. Results 3.1. Background data Patient characteristics are given in Table 1. Most study participants were female, and four out of ten individuals with CD had been diagnosed in childhood. 3.2. Suicide in coeliac disease During follow-up there were 54 suicides amongst individuals with CD (0.19%). The absolute rate of suicides amongst individuals with CD was 20/100,000 person-years with an excess risk of 7/100,000 person-years. Individuals with CD were hence at increased risk of suicide (HR = 1.55; 95%CI = 1.15–2.10) (Table 2).
Thirty-six percent of the suicides occurring in individuals with CD could be attributed to underlying CD (Table 2). The increased risk of suicide was most pronounced in the first year of follow-up (HR = 3.67; 95%CI = 1.60–8.39), but remained statistically significant also 5 years after first biopsy. Both men and women with CD were at increased risk of suicide (Table 3). Increased suicide risk was seen in all age groups with CD patients, although the HR only attained statistical significance amongst the eldest (Table 3). However, interaction testing found no interaction between CD suicide risk and age at biopsy (p = 0.975). Seven individuals diagnosed with CD as children died from suicide, corresponding to an HR of 1.42 (95%CI = 0.62–3.30). Individuals with CD were at increased risk of suicide across all three calendar periods, although only statistically significantly in 1990–1999 (Table 3). The association between CD and suicide was marginally attenuated after adjusting for lifetime depressive and anxiety disorder or for any psychiatric disorder but remained statistically significant (HR = 1.41; 95%CI = 1.02–1.96 and HR = 1.42; 95%CI = 1.00–1.99; p < 0.05). Adjusting for type 1 diabetes and autoimmune thyroid disease did not change the risk estimates (HR = 1.56; 95%CI = 1.15–2.12).
Undergoing biopsy, n=46,330 (29,148 with CD) (13,446 with inflammation) (3,736 with latent CD)
Included index individuals, n=46,065 (29,083 with CD*) (13,263 with inflammation#) (3,719 with latent CD¤)
Excluded, n=265
Biopsy potentially from ileum, n=174 Data irrgegularity: n=9 Lack of matched control=n=27 Biopsied after Dec 31, 2007: n=55
Controls, n=229,800
n=228,350
Excluded, n=1,450
Data irregularities, n=247 Not possible to match, n=928 Matched individual excluded, n=275.
Fig. 1. Flow chart of study participants. CD: coeliac disease and suicide. * 275 controls were excluded because their matched individuals undergoing biopsy had been excluded (and all analyses were matched on strata, see Section 2). # = Marsh 1–2.
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
619
Table 2 Relative and absolute risk of suicide by exposure and follow-up period in a Swedish nationwide retrospective cohort study of coeliac disease (CD). Exposure – Follow-up period
Events – observed
Events – expected
Hazard ratio 95%CI
p-value
Absolute risk rate per 100,000 person-years
Excess risk per 100,000 person-years
Population attributable fraction (%)
CD overall - Year <1 - Year 1–4.99 - Year ≥5 Inflammation overall - Year < 1 - Year 1–4.99 - Year ≥5 Normal mucosaa overall - Year <1 - Year 1–4.99 - Year ≥5
54 9 13 32 45 3 11 31 4
35 2 12 21 23 3 7 13 4
1.55: 1.15–2.10 3.67; 1.60–8.39 1.09; 0.60–1.96 1.56; 1.05–2.33 1.96; 1.39–2.77 1.12; 0.33–3.83 1.52; 0.77–2.94 2.45; 1.59–3.79 1.06; 0.37–3.02
0.005 0.002 0.778 0.027 <0.001 0.855 0.213 <0.001 0.913
20 31 13 22 42 24 28 56 16
7 23 1 8 21 3 10 33 1
36 73 8 36 49 11 34 59 6
0 4 0
0 2 0
– 2.25; 0.75–6.73 –
0.985 0.147 0.958
0 35 0
0 20 0
– 56 –
a
Normal mucosa but positive coeliac disease serology (IgA/IgG endomysium, tissue transglutaminase or gliadin antibodies).
3.3. Suicide in individuals with inflammation or normal mucosa but positive CD serology For reasons of comparison, we also estimated the risk of suicide amongst individuals who underwent biopsy but where the small intestinal mucosa had either shown inflammation without VA, or normal mucosa at the time of positive CD serology. Amongst the 3719 individuals with normal mucosa but positive CD serology, 369
were IgA EMA or IgA TTG+, whilst the others were gliadin+ or IgG EMA/TTG+. During follow-up, there were 45 suicides amongst individuals with inflammation (0.34%), and 4 amongst individuals with normal mucosa but positive CD serology (0.15%). All four individuals with normal mucosa but positive CD serology and suicide had positive antigliadin antibodies. Whilst individuals with inflammation were also at increased risk of death from suicide (HR = 1.96;
Table 3 Relative and absolute risk of suicide by patient and period characteristics in a Swedish nationwide retrospective cohort study of coeliac disease (CD). Characteristic
Sex Male
Female
Age at first biopsy <20
20–39
40–59
≥60
Year of first biopsy <1989
1990–1999
>2000
a
Exposure
Events – observed
Events – expected
Hazard ratio 95%CI
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
118 21 12 2 207 33 33 2
– 14 8 1 – 21 15 3
– 1.55; 0.96–2.52 1.55; 0.82–2.91 1.69; 0.38–7.50 – 1.55; 1.05–2.29 2.20; 1.46–3.32 0.76; 0.18–3.28
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
27 7 0 0 73 12 12 0 178 19 20 2 88 16 13 2
– 5 0 0 – 8 6 0 – 15 10 1 – 7 7 1
– 1.42; 0.62–3.30 – – – 1.49; 0.78–2.82 2.18; 1.12–4.26 – – 1.26; 0.76–2.08 1.93; 1.16–3.21 1.35; 0.30–6.05 – 2.34; 1.30–4.21 2.00; 1.03–3.90 2.65; 0.52–13.42
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
103 16 21 NA 157 30 20 1 65 8 4 3
– 13 7 – – 16 11 2 – 6 5 1
– 1.24; 0.72–2.15 3.01; 1.73–5.24 – – 1.89; 1.25–2.87 1.86; 1.12–3.08 0.43; 0.06–3.26 – 1.30; 0.60–2.77 0.86; 0.30–2.44 2.08; 0.59–7.36
p-value
Absolute risk rate per 100,000 person-years
Excess risk per 100,000 person-years
Population attributable fraction (%)
– 0.075 0.174 0.491 – 0.028 <0.001 0.712
– 12 20 13 – 32 69 21
– 4 7 5 – 11 38 –
– 36 35 41 – 35 55 –
– 0.409 0.985 0.991 – 0.225 0.023 0.974 – 0.368 0.011 0.693 – 0.004 0.041 0.239
– 6 0 0 – 24 38 0 – 30 54 30 – 43 47 65
– 2 0 0 – 8 21 0 – 6 26 8 – 25 24 41
– 30 – – – 33 54 – – 21 48 26 – 57 50 62
– 0.442 <0.001
– 20 66 – – 21 38 7 – 15 18 32
– 4 44 – – 10 17 – – 3 – 17
– 19 67 – – 47 46 – – 23 – 52
– 0.003 0.016 0.416 – 0.505 0.777 0.252
Normal mucosa but positive coeliac disease serology (IgA/IgG endomysium, tissue transglutaminase or gliadin antibodies).
620
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
95%CI = 1.39–2.77), those with normal mucosa but positive CD serology were not (HR = 1.06; 95%CI = = 0.37–3.02). There were no suicides amongst those who were children when diagnosed with inflammation or normal mucosa but positive CD serology. 3.4. Post-hoc analyses Using individuals with CD as reference (HR = 1.00), individuals with inflammation were at no statistically significantly increased risk of suicide (HR = 1.32; 95%CI = 0.88–1.97). The HR for suicide in normal mucosa but positive CD serology was 0.90 (95%CI = 0.32–2.52). 4. Discussion In this nationwide study of 29,000 patients with biopsy-verified CD, we found a moderately but significantly increased risk of suicide. The increased risk was seen both in individuals diagnosed as children and adults. In addition, suicide risk was higher amongst individuals with inflammation but no VA, but not in those with normal small intestinal mucosa but positive CD serology. CD diagnosed in childhood was associated with a 40% increase in suicide risk. Although absolute suicide rates were low in this group (6/100,000 person-years), one in three suicides amongst children with CD could be attributed to CD. Peters et al. [15] examined cause-specific death in a Swedish cohort of hospitalised CD patients and found a 1.8-fold increased risk of death (95%CI = 1.3–2.5) from external causes (44 deaths vs. 23.8 expected). However, suicide was not specifically examined. Other limitations of their study included the restriction to inpatients with CD, since they may suffer from more severe CD than the average CD patient. A British study recently reported seven deaths from accidents, suicide or violence in individuals diagnosed with CD in childhood (vs. 2.39 expected) [16] corresponding to a standardised mortality ratio of 2.39 (95%CI = 1.18–6.04), but found no such risk increase in adult CD. We had far greater statistical power (in all 250,000 person-years of follow-up compared to roughly 16,000 in the British study [16]), and found substantial risks also amongst adults. Thus, the risk for suicide amongst patients with CD seems to be increased in all age groups. The association between CD and suicide remained after adjustment for education or co-existing type 1 diabetes and autoimmune thyroid disease. The adjustment for type 1 diabetes is important since a recent study found that depression in CD may be especially common amongst CD patients with diabetes [25]. We used biopsy reports over a study period of 40 years. Although the diagnostic approach to CD (including advances in histopathology) has changed in these years this did not influence the risk estimates more than marginally (Table 3). The highest suicide risk in CD was seen in the first year after the diagnostic biopsy. Many CD patients have persisting small intestinal inflammation in the first year following diagnosis, despite adhering to a gluten-free diet [26], and this is likely to result in increased co-occurring morbidity including suicide. One potential explanation for our findings is relative malabsorption in patients with CD. Low cholesterol levels are associated with both CD [27] and suicide [28]. Specifically, Lewis et al. found a 21% decrease in cholesterol levels in men and a 9% decrease in women with CD [27]. However, early nutrition problems, for example related to intrauterine growth retardation, could also link CD [29] and suicide [30]. In addition, low BMI is associated with both CD [31] and suicide [32] or suicide attempt [33]. Another possible explanation concerns the increased risk of psychiatric disorder in CD [10,34], and that psychiatric disorder is a risk factor for suicide [35,36]. We previously found an 1.8-fold increased risk of unipo-
lar depression [10], and certain psychotic disorders [34] amongst patients with CD. Also, although the CD diagnosis was not confirmed by biopsy, a recent US study found higher prevalence of CD antibodies amongst individuals with schizophrenia [37]. However, suicide overrisks remained largely the same when we adjusted for lifetime depressive and anxiety disorder and any psychiatric disorder, respectively. This suggests that the link between CD and increased suicide risk is not primarily mediated by psychiatric morbidity. Active CD is characterised by VA and small intestinal inflammation, and a recent paper reported higher levels of several pro-inflammatory cytokines in the serum of CD patients [38]. This is notable given that high levels of IL-6 have also been found in the blood of individuals with depression [39] and the cerebrospinal fluid of suicide attempters [40], particularly those using violent methods [40]. In addition to the above mechanisms, poor quality of life [6,12], difficulties in adapting to the chronic nature of CD [6], and economic restraints caused by health care and adherence to a gluten-free diet [13] might contribute to the increased risk of suicide in CD. However, it should be underlined that the association between CD and suicide may not be causal, but due to shared risk factors (including elevation of pro-inflammatory cytokines). Some of the above associations may also be non-specific, and we cannot rule out that suicide is more frequently seen also in other gastrointestinal diseases than CD (as well as in other chronic diseases [41,42]). This may be especially relevant in diseases characterised by intestinal inflammation such as IBD since we found risk increases for suicide in both our two cohorts characterised by inflammation (patients with VA and patients without VA). We did however, not have access to suicide data in individuals with nonCD gastrointestinal disease since our main aim was to examine the risk of suicide in CD compared to that in the general population, and not compared to that in other gastrointestinal disease. The lack of nationwide coeliac disease serology data on asymptomatic individuals in Sweden means that our control group may include individuals with undiagnosed CD. This should however not affect our risk estimates since undiagnosed CD is unlikely to affect more than 1–2% of the population. We found an increased risk of suicide in individuals with inflammation but not in those with normal mucosa but positive CD serology. In a recent paper on overall mortality using the same data set as in this study [14], individuals with inflammation also had the highest risk for death from other cause than malignancy, cardiovascular disease or respiratory disease (standardised mortality ratio = 2.01; 95%CI = 1.82–2.21). In Sweden, traditionally, individuals without VA have not been put on a gluten-free diet [18]. Thus, it is possible that persistent inflammation increased both overall mortality rate and suicide risk. Using individuals with CD as the reference, suicide rates were not statistically significantly different in inflammation or in individuals with normal mucosa but positive CD serology. It could be that the risk of suicide is independent of small intestinal histopathology amongst individuals with CD or CD-like disease. Another potential explanation lies in the smaller statistical power in this post-hoc analysis. Amongst the strengths of this study is the use of biopsy registers to ascertain CD. Small intestinal biopsy is clinical practice in Sweden [18], and this avoided selection bias. VA is highly specific for CD, and a previous patient chart review found that 95% of patients with VA do have clinical CD [18]. The high positive predictive value of VA in biopsy registers was confirmed through the manual examination of more than 1500 biopsy reports [18] where another diagnosis than CD was very uncommon (the most common comorbidity mentioned in the biopsy reports were IBD in 0.3% of reports with VA and 1.6% in reports with inflamma-
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
tion. Helicobacter pylori was seen in 0.2% and 0.4%, respectively). The use of biopsy data also allowed us to study suicide amongst individuals with minor small intestine inflammation. This is important since these patients are not assigned an ICD code and cannot be followed through national health care registers. Still we cannot rule out a certain degree of misclassification. Artefacts can result in the appearance of shorter villi, with normal mucosa being classified as VA [43]. At the same time inclusion of false-positive individuals in our CD cohort will drive the risk estimate towards 1 and cannot explain the risk increase for suicide seen in this study. Although we did not require a positive CD serology for the diagnosis of CD, an earlier validation found that 88% of individuals with available CD serology data had positive serology at time of diagnosis [18]. However we were unable to compare the risk of suicide in those with VA and positive CD serology vs. those with negative CD serology since CD serology was obtained to identify individuals with normal mucosa but positive CD serology and not to define CD. This study also had some limitations. Although we were able to adjust for socioeconomic data, we lacked information on several potential confounders. Low BMI [32], low cholesterol [28], intrauterine growth retardation [30] and smoking [44] have all been linked to suicide. However, it may be argued that low BMI and low cholesterol are intermediates rather than confounders (page 122 [45]). We had no data on adherence to gluten-free diet and could not rule out that the increased suicide risk was restricted to individuals with low dietary compliance. The observation that individuals with normal mucosa but positive CD serology (normal mucosa) had no excess risk of suicide, whilst those with inflammation (and unlikely to have received a gluten-free diet [18]) had the highest risk of suicide is consistent with that possibility. Finish data suggest that gluten-free diet may otherwise alleviate depressive symptoms in adolescents with CD [46]. A recent report found that prior smoking (but not subsequent smoking) is linked to suicidality [44]. This should not explain our findings since most studies have found an inverse relationship between smoking and CD [47,48]. In the histopathology system that we used to collect data, inflammation in the duodenum and jejunum is equivalent to intraepithelial lymphocytosis; and a manual review of biopsy reports found that few individuals with inflammation had other comorbidity than CD [18]. Still we cannot rule out that some inflammation was unrelated to CD and instead due to, e.g. H. pylori infection, post-enteritis syndrome and IBD. Such misclassification might have influenced the HR for suicide and constitutes a limitation of our study. In this study positive CD serology denoted EMA, TTGA and antigliadin positivity, but suicides were only seen amongst individuals with positive antigliadin antibodies. For most of the follow-up of this study, antigliadin antibodies were the only available CD antibodies (and these individuals had the longest follow-up). Only in the late 1990s did Swedish biochemistry laboratories begin to use EMA (TTGA was introduced even later). In a large overview of 26 studies, Hill reported that the median specificity of antigliadin antibodies was 93–94% [49], and earlier validation of our data has found that symptoms and signs are similar amongst individuals with gliadin+ normal mucosa but positive CD serology and those with either EMA or TTGA [20]. The lack of suicides amongst individuals with EMA/TTGA argues against an increased risk of suicide. Still it should be noted that our data do not rule out an increased risk of suicide in this group, or amongst individuals with antigliadin positivity and normal mucosa since the 95% confidence interval included 1. The main purpose of this study was however to examine the risk of suicide in CD.
621
In conclusion, we found a moderately increased risk of suicide amongst patients with CD. This may warrant increased attention amongst physicians treating these patients. Conflict of interest statement None declared.
List of abbreviations CD, coeliac disease; CI, confidence interval; HR, Hazard ratio; VA, villous atrophy.
Acknowledgements JFL was supported by a grant from the Örebro University Hospital whilst writing this article. This project was supported by grants from The Swedish Society of Medicine, the Swedish Research Council – Medicine (522-2A09195), the Sven Jerring Foundation, the Örebro Society of Medicine, the Karolinska Institutet, the Clas Groschinsky Foundation, the Juhlin Foundation, the Majblomman Foundation, Uppsala-Örebro Regional Research Council and the Swedish Coeliac Society. Ethical approval: This project (2006/633-31/4) was approved by the Research Ethics Committee of the Karolinska Institute, Sweden on June 14th, 2006. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.dld.2011.02.009. References [1] Collin P, Kaukinen K, Valimaki M, et al. Endocrinological disorders and celiac disease. Endocr Rev 2002;23:464–83. [2] Ludvigsson JF, Olen O, Bell M, et al. Coeliac disease and risk of sepsis. Gut 2008;57:1074–80. [3] West J, Logan RF, Card TR, et al. Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 2003;125:429–36. [4] Addolorato G, Capristo E, Ghittoni G, et al. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001;36:502–6. [5] Siniscalchi M, Iovino P, Tortora R, et al. Fatigue in adult coeliac disease. Aliment Pharmacol Ther 2005;22:489–94. [6] 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;15:1287–92. [7] Ciacci C, Iavarone A, Mazzacca G, et al. Depressive symptoms in adult coeliac disease. Scand J Gastroenterol 1998;33:247–50. [8] Carta MG, Hardoy MC, Usai P, et al. Recurrent brief depression in celiac disease. J Psychosom Res 2003;55:573–4. [9] Accomando S, Fragapane ML, Montaperto D, et al. Coeliac disease and depression: two related entities? Dig Liver Dis 2005;37:298–9. [10] Ludvigsson JF, Reutfors J, Osby U, et al. Coeliac disease and risk of mood disorders—a general population-based cohort study. J Affect Disord 2007;99:117–26. [11] Hallert C, Astrom J, Sedvall G. Psychic disturbances in adult coeliac disease. III. Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol 1982;17:25–8. [12] Hallert C, Granno C, Grant C, et al. Quality of life of adult coeliac patients treated for 10 years. Scand J Gastroenterol 1998;33:933–8. [13] Lee AR, Ng DL, Zivin J, et al. Economic burden of a gluten-free diet. J Hum Nutr Diet 2007;20:423–30. [14] Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. J Am Med Assoc 2009;302:1171–8. [15] Peters U, Askling J, Gridley G, et al. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163:1566–72. [16] Solaymani-Dodaran M, West J, Logan RF. Long-term mortality in people with celiac disease diagnosed in childhood compared with adulthood: a populationbased cohort study. Am J Gastroenterol 2007;102:864–70. [17] Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, et al. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24:659–67.
622
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
[18] Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19. [19] Population in Sweden [working title: population coverage of university hospitals] [http://www.scb.se/pages/tableandchart 262456.aspx]. [20] Ludvigsson JF, Brandt L, Montgomery SM. Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa. BMC Gastroenterol 2009;9:57. [21] Johannesson I. The Total Population Register of Statistics Sweden. New possibilities and better quality. Örebro: Statistics Sweden; 2002. [22] Neeleman J, Wessely S. Changes in classification of suicide in England and Wales: time trends and associations with coroners’ professional backgrounds. Psychol Med 1997;27:467–72. [23] Westin M, Ahs A, Brand Persson K, et al. A large proportion of Swedish citizens refrain from seeking medical care—lack of confidence in the medical services a plausible explanation? Health Policy 2004;68:333–44. [24] Qin P, Agerbo E, Mortensen PB. Suicide risk in relation to socioeconomic, demographic, psychiatric, and familial factors: a national register-based study of all suicides in Denmark, 1981–1997. Am J Psychiatry 2003;160:765–72. [25] 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. [26] Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol 2008;6:314–20. [27] Lewis NR, Sanders DS, Logan RF, et al. Cholesterol profile in people with newly diagnosed coeliac disease: a comparison with the general population and changes following treatment. Br J Nutr 2009;102:509–13. [28] Partonen T, Haukka J, Virtamo J, et al. Association of low serum total cholesterol with major depression and suicide. Br J Psychiatry 1999;175:259–62. [29] Sandberg-Bennich S, Dahlquist G, Kallen B. Coeliac disease is associated with intrauterine growth and neonatal infections. Acta Paediatr 2002;91:30–3. [30] Mittendorfer-Rutz E, Rasmussen F, Wasserman D. Restricted fetal growth and adverse maternal psychosocial and socioeconomic conditions as risk factors for suicidal behaviour of offspring: a cohort study. Lancet 2004;364:1135–40. [31] Olen O, Montgomery SM, Marcus C, et al. Coeliac disease and body mass index: a study of two Swedish general population-based registers. Scand J Gastroenterol 2009:1–9. [32] Magnusson PK, Rasmussen F, Lawlor DA, et al. Association of body mass index with suicide mortality: a prospective cohort study of more than one million men. Am J Epidemiol 2006;163:1–8.
[33] Batty GD, Whitley E, Kivimaki M, et al. Body mass index and attempted suicide: cohort study of 1,133,019 Swedish men. Am J Epidemiol 2010;172:890–9. [34] Ludvigsson JF, Osby U, Ekbom A, et al. Coeliac disease and risk of schizophrenia and other psychosis: a general population cohort study. Scand J Gastroenterol 2007;42:179–85. [35] Rihmer Z. Suicide risk in mood disorders. Curr Opin Psychiatry 2007;20:17–22. [36] Hawton K, van Heeringen K. Suicide. Lancet 2009;373:1372–81. [37] Cascella NG, Kryszak D, Bhatti B, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull 2011;37:94–100. [38] Manavalan JS, Hernandez L, Shah JG, et al. Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol 2009;71: 50–7. [39] Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995;34:301–9. [40] Lindqvist D, Janelidze S, Hagell P, et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry 2009;66:287–92. [41] Barnes AJ, Eisenberg ME, Resnick MD. Suicide and self-injury among children and youth with chronic health conditions. Pediatrics 2010;125:889–95. [42] Pompili M, Serafini G, Di Cosimo D, et al. Psychiatric comorbidity and suicide risk in patients with chronic migraine. Neuropsychiatr Dis Treat 2010;6: 81–91. [43] Dickson BC, Streutker CJ, Chetty R. Coeliac disease: an update for pathologists. J Clin Pathol 2006;59:1008–16. [44] Bronisch T, Hofler M, Lieb R. Smoking predicts suicidality: findings from a prospective community study. J Affect Disord 2008;108:135–45. [45] Rothman K, Greenland S. Modern epidemiology. 2nd edn Philadelphia: Lippincott-Raven Publishers; 1998. [46] Pynnonen PA, Isometsa ET, Verkasalo MA, et al. Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with coeliac disease: a prospective follow-up case-series study. BMC Psychiatry 2005;5:14. [47] Suman S, Williams EJ, Thomas PW, et al. Is the risk of adult coeliac disease causally related to cigarette exposure? Eur J Gastroenterol Hepatol 2003;15:995–1000. [48] West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52:960–5. [49] Hill ID. What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? Gastroenterology 2005;128:S25–32.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Increased suicide risk in coeliac disease—A Swedish nationwide cohort study夽 Jonas F. Ludvigsson a,b,∗ , Carl Sellgren c , Bo Runeson d , Niklas Långström c,e , Paul Lichtenstein c a
Department of Paediatrics, Örebro University Hospital, Sweden Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden d Department of Clinical Neuroscience, Karolinska Institutet, Sweden e Centre for Violence Prevention, Karolinska Institutet, Sweden b
a r t i c l e
i n f o
Article history: Received 25 November 2010 Accepted 4 February 2011 Available online 17 March 2011 Keywords: Autoimmunity Coeliac Inflammation Suicide
a b s t r a c t Background and aim: Individuals with coeliac disease have increased risk of depression and death from external causes, but conclusive studies on death from suicide are missing. We examined the risk of suicide in coeliac disease and amongst individuals where the small intestinal biopsy showed no villous atrophy. Methods: We collected biopsy data from all 28 clinical pathology departments in Sweden for individuals diagnosed during 1969–2007 with coeliac disease (Marsh 3: villous atrophy; n = 29,083 unique individuals), inflammation without villous atrophy (Marsh 1–2; n = 13,263) or positive coeliac disease serology but normal mucosa (Marsh 0, n = 3719). Through Cox regression we calculated Hazard ratios for suicide as recorded in the Swedish Cause of Death Register. Results: The risk for suicide was higher in patients with coeliac disease compared to general population controls (HR = 1.55; 95%CI = 1.15–2.10; based on 54 completed suicides). Whilst suicide was also more common amongst individuals with inflammation (HR = 1.96; 95%CI = 1.39–2.77), no such increase was seen amongst individuals with a normal mucosa but positive coeliac disease serology (HR = 1.06; 95%CI = 0.37–3.02). Conclusions: We found a moderately increased risk of suicide amongst patients with coeliac disease. This merits increased attention amongst physicians treating these patients. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Coeliac disease (CD) is an immune-mediated disorder triggered by exposure to gluten. CD occurs in some 1/100 individuals, and is associated with a number of other somatic disorders including endocrine disease [1], sepsis [2] and osteoporosis [3]; but there are also several studies suggesting a positive association between CD and depression [4–10]. The mechanism behind the association between CD and depression may include conditions of the central nervous system [11], somatic comorbidity [1–3], poor quality of life [12], and economic restraints caused by health care and adherence to a gluten-free diet [13] – or a combination of these. Some data also indicate that the association with depression does not abate with a
夽 Disclaimer: None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Guarantor: JFL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. ∗ Corresponding author at: Department of Paediatrics, Örebro University Hospital, Sweden. Tel.: +46 (0) 19 6021000; fax: +46 (0) 19 187915. E-mail address: [email protected] (J.F. Ludvigsson).
gluten-free diet [4,7]. Since CD has been associated with psychiatric disorders, it is possible that patients with CD are at increased risk for suicide. In a recent paper, we found a 39% increased risk of overall death in CD [14]; most individuals died from cardiovascular disorder, malignancy and respiratory disease. However, other causes of death were also more common in individuals with CD (Hazard ratio, HR = 1.65; 95%CI = 1.51–1.81)[14]. We know of no large-scale studies on CD and suicide. An earlier Swedish study indicated an increased risk of death from external causes in CD [15], but that study was restricted to inpatients, and did not specifically examine the risk of suicide. A British study suggested an increased risk of death from accidents, suicides and violence in children, but not in adults, with CD [16]. Since the association between CD and suicide remains uncertain, we conducted a retrospective cohort study to compare the risk of suicide amongst 29,000 individuals in Sweden with biopsyverified CD (with villous atrophy, VA) during 1969–2007 with that amongst general population controls. For comparative reasons, we also estimated the risk of suicide in individuals with small intestinal inflammation but without VA, and those with normal mucosa but positive CD serology.
1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.02.009
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
2. Methods By using the unique Personal Identity Number (PIN) [17], we linked nationwide data on small intestine histopathology with data on suicide from the Swedish National Cause of Death Registry. Additional data were obtained from the National Hospital Discharge and Education Registries. The study was approved by the Research Ethics Committee of Karolinska Institutet. 2.1. Collection of biopsy data Between October 2006 and February 2008, we contacted all clinical pathology departments in Sweden (n = 28) to obtain data on duodenal/jejunal biopsy reports [18]. Local IT technicians performed searches, and delivered data on (a) arrival date of the biopsies, (b) PIN, (c) morphology according to Swedish SnoMed classification codes [18] and (d) topography (duodenum or jejunum). For the purpose of this paper, SnoMed codes were translated into corresponding Marsh stages (see Appendix). Data searches were restricted to computerised records; hence, the majority of patients in this study were biopsied after 1990 (Table 1). Small intestinal morphology was graded into VA (Marsh stage 3, and equal to CD), inflammation without VA (Marsh 1–2) and normal mucosa (Marsh 0). A detailed list of relevant morphology codes has been published elsewhere [18] (see also Appendix). We based the CD diagnosis solely on small intestinal morphology; positive CD serology was not required for the diagnosis. For a diagnosis of inflammation, we required a SnoMed code corresponding to duodenal/jejunal inflammation [18] but no biopsy-verified VA. In the most commonly used Swedish histopathology classification (“KVAST” – the Swedish committee on quality and standardisation), inflammation is equivalent to intraepithelial lymphocytosis. The Swedish classification does not distinguish between Marsh 1 and 2. In this study, we used the same dataset as in a recent paper on overall mortality in CD [14]. After the exclusion of duplicates and biopsies with data irregularities (e.g. a biopsy seemingly performed before birth or after the death of an individual), we had data from 351,403 biopsy reports in 287,586 unique individuals (CD: 29,148; inflammation: 13,446 and normal biopsy: 244,992). Individuals with normal mucosa but positive CD serology were identified through linkage of biopsy report data (in a subset of individuals with normal mucosa, n = 121,952) with positive CD serology data from eight university hospitals in Sweden. Although these hospitals care for 49% of the Swedish population [19], living in both urban and rural areas, data on normal mucosa but positive CD serology were hence regional, not nationwide. Through this linkage, we obtained data on date of test, type of test [antigliadin, endomysial (EMA), tissue transglutaminase (TTG)], antibody levels, IgA/IgG ratios and age-specific reference values at the time of testing for all individuals with normal mucosa [20]. In this study, we defined “positive CD serology” as positive when obtained up to 180 days before a normal biopsy, and until 30 days after such biopsy [20] in individuals who never had a biopsy with VA or inflammation; 3736 individuals fulfilled these criteria [20]. Hence, individuals with more than one biopsy were defined according to the biopsy with the highest Marsh grade (most severe histopathology). Data on each individual undergoing biopsy (total n = 46,330) were sent for matching by the government agency Statistics Sweden. Additional exclusions are presented in Fig. 1. 2.2. Reference individuals Each individual undergoing biopsy was matched with up to five reference individuals by age, sex, county and calendar year
617
through the Total Population Register [21]. All Swedish residents who had had no recorded biopsy with CD, inflammation or normal mucosa but positive CD serology when their matched index individual underwent biopsy were eligible as reference individuals. In total, Statistics Sweden identified 229,800 reference individuals. We then excluded individuals with data irregularities or since they could not be matched with any individual undergoing biopsy (Fig. 1). In all, this study was based on 29,083 individuals with CD, 13,263 with inflammation, 3719 with normal mucosa but positive CD serology and 228,350 general population reference individuals. 2.3. Outcome measure We used ICD E-codes to define suicide in the longitudinal Cause of Death Register (operative from 1953): ICD-8 and ICD-9: E-codes 950-959 and 980-989; ICD-10: X60-X85 and Y10-34. We included both certain and uncertain suicides since the exclusion of uncertain suicides may lead to an underestimation of true suicides [22]. In 1995, the National Board of Health and Welfare received death certificates on 99.7% of all deaths, suggesting excellent coverage. 2.4. Other covariates Through relevant ICD codes in the Hospital Discharge Register we identified study participants with type 1 diabetes, autoimmune thyroid disease, depressive disorders, anxiety or phobic disorders as well as any psychiatric disorder (see Appendix). Education: To adjust for education, we used seven predefined levels, ranging from not completed 9-year compulsory school to PhD-degree, obtained from the Education Register. 2.5. Statistical analyses Cox regression modelling provided HRs for death from suicide. The Cox regression was internally stratified; the index individual was only compared with his/her reference individuals within the same stratum; and then a summary risk estimate was calculated. The proportional hazards assumption was tested through plotting logminuslog curves. Follow-up began on date of first positive biopsy (CD, inflammation or normal mucosa in an individual with positive CD serology at time of biopsy) and corresponding date in matched reference individuals. Follow-up ended with death from suicide, death from other cause, emigration or on December 31st 2007, whichever happened first. In reference individuals, follow-up could also end if the individual had a biopsy with CD or inflammation, or normal mucosa but positive CD serology after matching had occurred. In a priori subanalyses, we examined the risk of suicide by follow-up period (<1 year, 1–4.99 and ≥5 years), sex, age (0–19, 20–39, 40–59 and ≥60 years at first biopsy), and calendar period of first biopsy (–1989, 1990–1999 and 2000–). We calculated incidence rates as number of suicides divided by person-years at risk. In separate analyses, we adjusted for type 1 diabetes and autoimmune thyroid disease as well as education. Both type 1 diabetes and autoimmune thyroid disease could influence hospital admission patterns amongst individuals with CD and potentially also the risk of suicide. Education or socioeconomic status may also influence health care use (and ascertainment of CD) [23], and risk of suicide [24]. To estimate the influence of psychiatric disorder on the risk of suicide in patients with CD, we adjusted for psychiatric disorder in two analyses. Firstly, we adjusted for an inpatient diagnosis of a depressive or anxiety disorder at some stage of life from 1973 and onwards. Secondly, we adjusted for any lifetime psychiatric disorder.
618
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
Table 1 Characteristics of study participants in a Swedish nationwide retrospective cohort study of suicide in coeliac disease. Characteristic
Coeliac disease (N = 29,083) Inflammation (N = 13,263) Normal mucosa but positive CD serologya (N = 3,719)
Female sex (%) Male sex (%) Age at study entry, years (median; range) Age 0–19 (%) Age 20–39 (%) Age 40–59 (%) Age ≥60 (%) Entry year (median; range) Calendar year for diagnosis –1989 (%) 1990–1999 (%) 2000– (%) Follow-up, years (median; range) Follow-up, years (mean; SD) Diagnosis of type 1 diabetes (%) Lifetime diagnosis of depressive or anxiety disorder (%) Lifetime diagnosis of any psychiatric disorder (%)
17,997 (61.9) 11,086 (38.1) 40; 1–100 11,798 (40.6) 5,309 (18.3) 6,473 (22.3) 5,503 (18.9) 1998; 1969–2007
7,469 (56.3) 5,764 (43.7) 59; 2–104 1,224 (9.2) 3,529 (26.6) 4,133 (31.2) 4,377 (33.0) 1999; 1970–2007
2,310 (62.1) 1,409 (37.9) 43; 2–97 941 (25.3) 1,150 (30.9) 1,064 (28.6) 564 (15.2) 2001; 1990–2007
4,105 (14.1) 12,059 (41.5) 12,919 (44.4) 8.1; 0–38.5 9.4; 6.4 1,319 (4.5) 1,019 (3.5) 2,240 (7.7)
1,961 (14.8) 5,164 (38.9) 6,138 (46.3) 6.6; 0–32.7 8.0; 6.5 440 (3.3) 849 (6.4) 1,633 (12.3)
0 (0) 1,387 (37.2) 2,332 (62.7) 5.9; 0–17.8 6.7; 4.3 111 (3.0) 151 (4.1) 337 (9.1)
Note: CD (coeliac disease) serology included IgA/IgG gliadin, endomysial and tissue transglutaminase antibodies.
2.6. Post-hoc analyses In a post-hoc analysis we examined the risk of suicide in CD vs. inflammation and normal mucosa but positive CD serology adjusting for sex, age at biopsy and calendar year at biopsy. We used SPSS 16.0 to perform all analyses. HRs with 95%CIs not including 1 were regarded as statistically significant. 3. Results 3.1. Background data Patient characteristics are given in Table 1. Most study participants were female, and four out of ten individuals with CD had been diagnosed in childhood. 3.2. Suicide in coeliac disease During follow-up there were 54 suicides amongst individuals with CD (0.19%). The absolute rate of suicides amongst individuals with CD was 20/100,000 person-years with an excess risk of 7/100,000 person-years. Individuals with CD were hence at increased risk of suicide (HR = 1.55; 95%CI = 1.15–2.10) (Table 2).
Thirty-six percent of the suicides occurring in individuals with CD could be attributed to underlying CD (Table 2). The increased risk of suicide was most pronounced in the first year of follow-up (HR = 3.67; 95%CI = 1.60–8.39), but remained statistically significant also 5 years after first biopsy. Both men and women with CD were at increased risk of suicide (Table 3). Increased suicide risk was seen in all age groups with CD patients, although the HR only attained statistical significance amongst the eldest (Table 3). However, interaction testing found no interaction between CD suicide risk and age at biopsy (p = 0.975). Seven individuals diagnosed with CD as children died from suicide, corresponding to an HR of 1.42 (95%CI = 0.62–3.30). Individuals with CD were at increased risk of suicide across all three calendar periods, although only statistically significantly in 1990–1999 (Table 3). The association between CD and suicide was marginally attenuated after adjusting for lifetime depressive and anxiety disorder or for any psychiatric disorder but remained statistically significant (HR = 1.41; 95%CI = 1.02–1.96 and HR = 1.42; 95%CI = 1.00–1.99; p < 0.05). Adjusting for type 1 diabetes and autoimmune thyroid disease did not change the risk estimates (HR = 1.56; 95%CI = 1.15–2.12).
Undergoing biopsy, n=46,330 (29,148 with CD) (13,446 with inflammation) (3,736 with latent CD)
Included index individuals, n=46,065 (29,083 with CD*) (13,263 with inflammation#) (3,719 with latent CD¤)
Excluded, n=265
Biopsy potentially from ileum, n=174 Data irrgegularity: n=9 Lack of matched control=n=27 Biopsied after Dec 31, 2007: n=55
Controls, n=229,800
n=228,350
Excluded, n=1,450
Data irregularities, n=247 Not possible to match, n=928 Matched individual excluded, n=275.
Fig. 1. Flow chart of study participants. CD: coeliac disease and suicide. * 275 controls were excluded because their matched individuals undergoing biopsy had been excluded (and all analyses were matched on strata, see Section 2). # = Marsh 1–2.
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
619
Table 2 Relative and absolute risk of suicide by exposure and follow-up period in a Swedish nationwide retrospective cohort study of coeliac disease (CD). Exposure – Follow-up period
Events – observed
Events – expected
Hazard ratio 95%CI
p-value
Absolute risk rate per 100,000 person-years
Excess risk per 100,000 person-years
Population attributable fraction (%)
CD overall - Year <1 - Year 1–4.99 - Year ≥5 Inflammation overall - Year < 1 - Year 1–4.99 - Year ≥5 Normal mucosaa overall - Year <1 - Year 1–4.99 - Year ≥5
54 9 13 32 45 3 11 31 4
35 2 12 21 23 3 7 13 4
1.55: 1.15–2.10 3.67; 1.60–8.39 1.09; 0.60–1.96 1.56; 1.05–2.33 1.96; 1.39–2.77 1.12; 0.33–3.83 1.52; 0.77–2.94 2.45; 1.59–3.79 1.06; 0.37–3.02
0.005 0.002 0.778 0.027 <0.001 0.855 0.213 <0.001 0.913
20 31 13 22 42 24 28 56 16
7 23 1 8 21 3 10 33 1
36 73 8 36 49 11 34 59 6
0 4 0
0 2 0
– 2.25; 0.75–6.73 –
0.985 0.147 0.958
0 35 0
0 20 0
– 56 –
a
Normal mucosa but positive coeliac disease serology (IgA/IgG endomysium, tissue transglutaminase or gliadin antibodies).
3.3. Suicide in individuals with inflammation or normal mucosa but positive CD serology For reasons of comparison, we also estimated the risk of suicide amongst individuals who underwent biopsy but where the small intestinal mucosa had either shown inflammation without VA, or normal mucosa at the time of positive CD serology. Amongst the 3719 individuals with normal mucosa but positive CD serology, 369
were IgA EMA or IgA TTG+, whilst the others were gliadin+ or IgG EMA/TTG+. During follow-up, there were 45 suicides amongst individuals with inflammation (0.34%), and 4 amongst individuals with normal mucosa but positive CD serology (0.15%). All four individuals with normal mucosa but positive CD serology and suicide had positive antigliadin antibodies. Whilst individuals with inflammation were also at increased risk of death from suicide (HR = 1.96;
Table 3 Relative and absolute risk of suicide by patient and period characteristics in a Swedish nationwide retrospective cohort study of coeliac disease (CD). Characteristic
Sex Male
Female
Age at first biopsy <20
20–39
40–59
≥60
Year of first biopsy <1989
1990–1999
>2000
a
Exposure
Events – observed
Events – expected
Hazard ratio 95%CI
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
118 21 12 2 207 33 33 2
– 14 8 1 – 21 15 3
– 1.55; 0.96–2.52 1.55; 0.82–2.91 1.69; 0.38–7.50 – 1.55; 1.05–2.29 2.20; 1.46–3.32 0.76; 0.18–3.28
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
27 7 0 0 73 12 12 0 178 19 20 2 88 16 13 2
– 5 0 0 – 8 6 0 – 15 10 1 – 7 7 1
– 1.42; 0.62–3.30 – – – 1.49; 0.78–2.82 2.18; 1.12–4.26 – – 1.26; 0.76–2.08 1.93; 1.16–3.21 1.35; 0.30–6.05 – 2.34; 1.30–4.21 2.00; 1.03–3.90 2.65; 0.52–13.42
Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa Reference CD Inflammation Normal mucosaa
103 16 21 NA 157 30 20 1 65 8 4 3
– 13 7 – – 16 11 2 – 6 5 1
– 1.24; 0.72–2.15 3.01; 1.73–5.24 – – 1.89; 1.25–2.87 1.86; 1.12–3.08 0.43; 0.06–3.26 – 1.30; 0.60–2.77 0.86; 0.30–2.44 2.08; 0.59–7.36
p-value
Absolute risk rate per 100,000 person-years
Excess risk per 100,000 person-years
Population attributable fraction (%)
– 0.075 0.174 0.491 – 0.028 <0.001 0.712
– 12 20 13 – 32 69 21
– 4 7 5 – 11 38 –
– 36 35 41 – 35 55 –
– 0.409 0.985 0.991 – 0.225 0.023 0.974 – 0.368 0.011 0.693 – 0.004 0.041 0.239
– 6 0 0 – 24 38 0 – 30 54 30 – 43 47 65
– 2 0 0 – 8 21 0 – 6 26 8 – 25 24 41
– 30 – – – 33 54 – – 21 48 26 – 57 50 62
– 0.442 <0.001
– 20 66 – – 21 38 7 – 15 18 32
– 4 44 – – 10 17 – – 3 – 17
– 19 67 – – 47 46 – – 23 – 52
– 0.003 0.016 0.416 – 0.505 0.777 0.252
Normal mucosa but positive coeliac disease serology (IgA/IgG endomysium, tissue transglutaminase or gliadin antibodies).
620
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
95%CI = 1.39–2.77), those with normal mucosa but positive CD serology were not (HR = 1.06; 95%CI = = 0.37–3.02). There were no suicides amongst those who were children when diagnosed with inflammation or normal mucosa but positive CD serology. 3.4. Post-hoc analyses Using individuals with CD as reference (HR = 1.00), individuals with inflammation were at no statistically significantly increased risk of suicide (HR = 1.32; 95%CI = 0.88–1.97). The HR for suicide in normal mucosa but positive CD serology was 0.90 (95%CI = 0.32–2.52). 4. Discussion In this nationwide study of 29,000 patients with biopsy-verified CD, we found a moderately but significantly increased risk of suicide. The increased risk was seen both in individuals diagnosed as children and adults. In addition, suicide risk was higher amongst individuals with inflammation but no VA, but not in those with normal small intestinal mucosa but positive CD serology. CD diagnosed in childhood was associated with a 40% increase in suicide risk. Although absolute suicide rates were low in this group (6/100,000 person-years), one in three suicides amongst children with CD could be attributed to CD. Peters et al. [15] examined cause-specific death in a Swedish cohort of hospitalised CD patients and found a 1.8-fold increased risk of death (95%CI = 1.3–2.5) from external causes (44 deaths vs. 23.8 expected). However, suicide was not specifically examined. Other limitations of their study included the restriction to inpatients with CD, since they may suffer from more severe CD than the average CD patient. A British study recently reported seven deaths from accidents, suicide or violence in individuals diagnosed with CD in childhood (vs. 2.39 expected) [16] corresponding to a standardised mortality ratio of 2.39 (95%CI = 1.18–6.04), but found no such risk increase in adult CD. We had far greater statistical power (in all 250,000 person-years of follow-up compared to roughly 16,000 in the British study [16]), and found substantial risks also amongst adults. Thus, the risk for suicide amongst patients with CD seems to be increased in all age groups. The association between CD and suicide remained after adjustment for education or co-existing type 1 diabetes and autoimmune thyroid disease. The adjustment for type 1 diabetes is important since a recent study found that depression in CD may be especially common amongst CD patients with diabetes [25]. We used biopsy reports over a study period of 40 years. Although the diagnostic approach to CD (including advances in histopathology) has changed in these years this did not influence the risk estimates more than marginally (Table 3). The highest suicide risk in CD was seen in the first year after the diagnostic biopsy. Many CD patients have persisting small intestinal inflammation in the first year following diagnosis, despite adhering to a gluten-free diet [26], and this is likely to result in increased co-occurring morbidity including suicide. One potential explanation for our findings is relative malabsorption in patients with CD. Low cholesterol levels are associated with both CD [27] and suicide [28]. Specifically, Lewis et al. found a 21% decrease in cholesterol levels in men and a 9% decrease in women with CD [27]. However, early nutrition problems, for example related to intrauterine growth retardation, could also link CD [29] and suicide [30]. In addition, low BMI is associated with both CD [31] and suicide [32] or suicide attempt [33]. Another possible explanation concerns the increased risk of psychiatric disorder in CD [10,34], and that psychiatric disorder is a risk factor for suicide [35,36]. We previously found an 1.8-fold increased risk of unipo-
lar depression [10], and certain psychotic disorders [34] amongst patients with CD. Also, although the CD diagnosis was not confirmed by biopsy, a recent US study found higher prevalence of CD antibodies amongst individuals with schizophrenia [37]. However, suicide overrisks remained largely the same when we adjusted for lifetime depressive and anxiety disorder and any psychiatric disorder, respectively. This suggests that the link between CD and increased suicide risk is not primarily mediated by psychiatric morbidity. Active CD is characterised by VA and small intestinal inflammation, and a recent paper reported higher levels of several pro-inflammatory cytokines in the serum of CD patients [38]. This is notable given that high levels of IL-6 have also been found in the blood of individuals with depression [39] and the cerebrospinal fluid of suicide attempters [40], particularly those using violent methods [40]. In addition to the above mechanisms, poor quality of life [6,12], difficulties in adapting to the chronic nature of CD [6], and economic restraints caused by health care and adherence to a gluten-free diet [13] might contribute to the increased risk of suicide in CD. However, it should be underlined that the association between CD and suicide may not be causal, but due to shared risk factors (including elevation of pro-inflammatory cytokines). Some of the above associations may also be non-specific, and we cannot rule out that suicide is more frequently seen also in other gastrointestinal diseases than CD (as well as in other chronic diseases [41,42]). This may be especially relevant in diseases characterised by intestinal inflammation such as IBD since we found risk increases for suicide in both our two cohorts characterised by inflammation (patients with VA and patients without VA). We did however, not have access to suicide data in individuals with nonCD gastrointestinal disease since our main aim was to examine the risk of suicide in CD compared to that in the general population, and not compared to that in other gastrointestinal disease. The lack of nationwide coeliac disease serology data on asymptomatic individuals in Sweden means that our control group may include individuals with undiagnosed CD. This should however not affect our risk estimates since undiagnosed CD is unlikely to affect more than 1–2% of the population. We found an increased risk of suicide in individuals with inflammation but not in those with normal mucosa but positive CD serology. In a recent paper on overall mortality using the same data set as in this study [14], individuals with inflammation also had the highest risk for death from other cause than malignancy, cardiovascular disease or respiratory disease (standardised mortality ratio = 2.01; 95%CI = 1.82–2.21). In Sweden, traditionally, individuals without VA have not been put on a gluten-free diet [18]. Thus, it is possible that persistent inflammation increased both overall mortality rate and suicide risk. Using individuals with CD as the reference, suicide rates were not statistically significantly different in inflammation or in individuals with normal mucosa but positive CD serology. It could be that the risk of suicide is independent of small intestinal histopathology amongst individuals with CD or CD-like disease. Another potential explanation lies in the smaller statistical power in this post-hoc analysis. Amongst the strengths of this study is the use of biopsy registers to ascertain CD. Small intestinal biopsy is clinical practice in Sweden [18], and this avoided selection bias. VA is highly specific for CD, and a previous patient chart review found that 95% of patients with VA do have clinical CD [18]. The high positive predictive value of VA in biopsy registers was confirmed through the manual examination of more than 1500 biopsy reports [18] where another diagnosis than CD was very uncommon (the most common comorbidity mentioned in the biopsy reports were IBD in 0.3% of reports with VA and 1.6% in reports with inflamma-
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
tion. Helicobacter pylori was seen in 0.2% and 0.4%, respectively). The use of biopsy data also allowed us to study suicide amongst individuals with minor small intestine inflammation. This is important since these patients are not assigned an ICD code and cannot be followed through national health care registers. Still we cannot rule out a certain degree of misclassification. Artefacts can result in the appearance of shorter villi, with normal mucosa being classified as VA [43]. At the same time inclusion of false-positive individuals in our CD cohort will drive the risk estimate towards 1 and cannot explain the risk increase for suicide seen in this study. Although we did not require a positive CD serology for the diagnosis of CD, an earlier validation found that 88% of individuals with available CD serology data had positive serology at time of diagnosis [18]. However we were unable to compare the risk of suicide in those with VA and positive CD serology vs. those with negative CD serology since CD serology was obtained to identify individuals with normal mucosa but positive CD serology and not to define CD. This study also had some limitations. Although we were able to adjust for socioeconomic data, we lacked information on several potential confounders. Low BMI [32], low cholesterol [28], intrauterine growth retardation [30] and smoking [44] have all been linked to suicide. However, it may be argued that low BMI and low cholesterol are intermediates rather than confounders (page 122 [45]). We had no data on adherence to gluten-free diet and could not rule out that the increased suicide risk was restricted to individuals with low dietary compliance. The observation that individuals with normal mucosa but positive CD serology (normal mucosa) had no excess risk of suicide, whilst those with inflammation (and unlikely to have received a gluten-free diet [18]) had the highest risk of suicide is consistent with that possibility. Finish data suggest that gluten-free diet may otherwise alleviate depressive symptoms in adolescents with CD [46]. A recent report found that prior smoking (but not subsequent smoking) is linked to suicidality [44]. This should not explain our findings since most studies have found an inverse relationship between smoking and CD [47,48]. In the histopathology system that we used to collect data, inflammation in the duodenum and jejunum is equivalent to intraepithelial lymphocytosis; and a manual review of biopsy reports found that few individuals with inflammation had other comorbidity than CD [18]. Still we cannot rule out that some inflammation was unrelated to CD and instead due to, e.g. H. pylori infection, post-enteritis syndrome and IBD. Such misclassification might have influenced the HR for suicide and constitutes a limitation of our study. In this study positive CD serology denoted EMA, TTGA and antigliadin positivity, but suicides were only seen amongst individuals with positive antigliadin antibodies. For most of the follow-up of this study, antigliadin antibodies were the only available CD antibodies (and these individuals had the longest follow-up). Only in the late 1990s did Swedish biochemistry laboratories begin to use EMA (TTGA was introduced even later). In a large overview of 26 studies, Hill reported that the median specificity of antigliadin antibodies was 93–94% [49], and earlier validation of our data has found that symptoms and signs are similar amongst individuals with gliadin+ normal mucosa but positive CD serology and those with either EMA or TTGA [20]. The lack of suicides amongst individuals with EMA/TTGA argues against an increased risk of suicide. Still it should be noted that our data do not rule out an increased risk of suicide in this group, or amongst individuals with antigliadin positivity and normal mucosa since the 95% confidence interval included 1. The main purpose of this study was however to examine the risk of suicide in CD.
621
In conclusion, we found a moderately increased risk of suicide amongst patients with CD. This may warrant increased attention amongst physicians treating these patients. Conflict of interest statement None declared.
List of abbreviations CD, coeliac disease; CI, confidence interval; HR, Hazard ratio; VA, villous atrophy.
Acknowledgements JFL was supported by a grant from the Örebro University Hospital whilst writing this article. This project was supported by grants from The Swedish Society of Medicine, the Swedish Research Council – Medicine (522-2A09195), the Sven Jerring Foundation, the Örebro Society of Medicine, the Karolinska Institutet, the Clas Groschinsky Foundation, the Juhlin Foundation, the Majblomman Foundation, Uppsala-Örebro Regional Research Council and the Swedish Coeliac Society. Ethical approval: This project (2006/633-31/4) was approved by the Research Ethics Committee of the Karolinska Institute, Sweden on June 14th, 2006. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.dld.2011.02.009. References [1] Collin P, Kaukinen K, Valimaki M, et al. Endocrinological disorders and celiac disease. Endocr Rev 2002;23:464–83. [2] Ludvigsson JF, Olen O, Bell M, et al. Coeliac disease and risk of sepsis. Gut 2008;57:1074–80. [3] West J, Logan RF, Card TR, et al. Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 2003;125:429–36. [4] Addolorato G, Capristo E, Ghittoni G, et al. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001;36:502–6. [5] Siniscalchi M, Iovino P, Tortora R, et al. Fatigue in adult coeliac disease. Aliment Pharmacol Ther 2005;22:489–94. [6] 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;15:1287–92. [7] Ciacci C, Iavarone A, Mazzacca G, et al. Depressive symptoms in adult coeliac disease. Scand J Gastroenterol 1998;33:247–50. [8] Carta MG, Hardoy MC, Usai P, et al. Recurrent brief depression in celiac disease. J Psychosom Res 2003;55:573–4. [9] Accomando S, Fragapane ML, Montaperto D, et al. Coeliac disease and depression: two related entities? Dig Liver Dis 2005;37:298–9. [10] Ludvigsson JF, Reutfors J, Osby U, et al. Coeliac disease and risk of mood disorders—a general population-based cohort study. J Affect Disord 2007;99:117–26. [11] Hallert C, Astrom J, Sedvall G. Psychic disturbances in adult coeliac disease. III. Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol 1982;17:25–8. [12] Hallert C, Granno C, Grant C, et al. Quality of life of adult coeliac patients treated for 10 years. Scand J Gastroenterol 1998;33:933–8. [13] Lee AR, Ng DL, Zivin J, et al. Economic burden of a gluten-free diet. J Hum Nutr Diet 2007;20:423–30. [14] Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. J Am Med Assoc 2009;302:1171–8. [15] Peters U, Askling J, Gridley G, et al. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163:1566–72. [16] Solaymani-Dodaran M, West J, Logan RF. Long-term mortality in people with celiac disease diagnosed in childhood compared with adulthood: a populationbased cohort study. Am J Gastroenterol 2007;102:864–70. [17] Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, et al. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24:659–67.
622
J.F. Ludvigsson et al. / Digestive and Liver Disease 43 (2011) 616–622
[18] Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19. [19] Population in Sweden [working title: population coverage of university hospitals] [http://www.scb.se/pages/tableandchart 262456.aspx]. [20] Ludvigsson JF, Brandt L, Montgomery SM. Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa. BMC Gastroenterol 2009;9:57. [21] Johannesson I. The Total Population Register of Statistics Sweden. New possibilities and better quality. Örebro: Statistics Sweden; 2002. [22] Neeleman J, Wessely S. Changes in classification of suicide in England and Wales: time trends and associations with coroners’ professional backgrounds. Psychol Med 1997;27:467–72. [23] Westin M, Ahs A, Brand Persson K, et al. A large proportion of Swedish citizens refrain from seeking medical care—lack of confidence in the medical services a plausible explanation? Health Policy 2004;68:333–44. [24] Qin P, Agerbo E, Mortensen PB. Suicide risk in relation to socioeconomic, demographic, psychiatric, and familial factors: a national register-based study of all suicides in Denmark, 1981–1997. Am J Psychiatry 2003;160:765–72. [25] 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. [26] Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol 2008;6:314–20. [27] Lewis NR, Sanders DS, Logan RF, et al. Cholesterol profile in people with newly diagnosed coeliac disease: a comparison with the general population and changes following treatment. Br J Nutr 2009;102:509–13. [28] Partonen T, Haukka J, Virtamo J, et al. Association of low serum total cholesterol with major depression and suicide. Br J Psychiatry 1999;175:259–62. [29] Sandberg-Bennich S, Dahlquist G, Kallen B. Coeliac disease is associated with intrauterine growth and neonatal infections. Acta Paediatr 2002;91:30–3. [30] Mittendorfer-Rutz E, Rasmussen F, Wasserman D. Restricted fetal growth and adverse maternal psychosocial and socioeconomic conditions as risk factors for suicidal behaviour of offspring: a cohort study. Lancet 2004;364:1135–40. [31] Olen O, Montgomery SM, Marcus C, et al. Coeliac disease and body mass index: a study of two Swedish general population-based registers. Scand J Gastroenterol 2009:1–9. [32] Magnusson PK, Rasmussen F, Lawlor DA, et al. Association of body mass index with suicide mortality: a prospective cohort study of more than one million men. Am J Epidemiol 2006;163:1–8.
[33] Batty GD, Whitley E, Kivimaki M, et al. Body mass index and attempted suicide: cohort study of 1,133,019 Swedish men. Am J Epidemiol 2010;172:890–9. [34] Ludvigsson JF, Osby U, Ekbom A, et al. Coeliac disease and risk of schizophrenia and other psychosis: a general population cohort study. Scand J Gastroenterol 2007;42:179–85. [35] Rihmer Z. Suicide risk in mood disorders. Curr Opin Psychiatry 2007;20:17–22. [36] Hawton K, van Heeringen K. Suicide. Lancet 2009;373:1372–81. [37] Cascella NG, Kryszak D, Bhatti B, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull 2011;37:94–100. [38] Manavalan JS, Hernandez L, Shah JG, et al. Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol 2009;71: 50–7. [39] Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995;34:301–9. [40] Lindqvist D, Janelidze S, Hagell P, et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry 2009;66:287–92. [41] Barnes AJ, Eisenberg ME, Resnick MD. Suicide and self-injury among children and youth with chronic health conditions. Pediatrics 2010;125:889–95. [42] Pompili M, Serafini G, Di Cosimo D, et al. Psychiatric comorbidity and suicide risk in patients with chronic migraine. Neuropsychiatr Dis Treat 2010;6: 81–91. [43] Dickson BC, Streutker CJ, Chetty R. Coeliac disease: an update for pathologists. J Clin Pathol 2006;59:1008–16. [44] Bronisch T, Hofler M, Lieb R. Smoking predicts suicidality: findings from a prospective community study. J Affect Disord 2008;108:135–45. [45] Rothman K, Greenland S. Modern epidemiology. 2nd edn Philadelphia: Lippincott-Raven Publishers; 1998. [46] Pynnonen PA, Isometsa ET, Verkasalo MA, et al. Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with coeliac disease: a prospective follow-up case-series study. BMC Psychiatry 2005;5:14. [47] Suman S, Williams EJ, Thomas PW, et al. Is the risk of adult coeliac disease causally related to cigarette exposure? Eur J Gastroenterol Hepatol 2003;15:995–1000. [48] West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52:960–5. [49] Hill ID. What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? Gastroenterology 2005;128:S25–32.