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Keywords:

  • cause-specific death;
  • coeliac disease;
  • cohort studies;
  • mortality;
  • type 1 diabetes

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

Aim

The aim of this study was to examine mortality in patients with both type 1 diabetes (T1D) and coeliac disease (CD).

Methods

Between 1969 and 2008, we identified individuals with CD through biopsy reports from all pathology departments (= 28) in Sweden. T1D was defined as a diagnosis of diabetes recorded in the Swedish National Patient Register between 1964 and 2009 in individuals aged ≤30 years. During follow-up, we identified 960 patients with both T1D and CD. For each individual with T1D and CD, we selected up to five subjects with T1D alone (i.e. no CD), matched for sex, age and calendar period of diagnosis, as the reference group (= 4608). Using a stratified Cox regression analysis with CD as a time-dependent covariate, we estimated the risk of death in patients with both T1D and CD compared with those with T1D alone.

Results

Stratifying for time since CD diagnosis, CD was not a risk factor for death in patients with T1D during the first 5 years after CD diagnosis [hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.43–1.73], but thereafter the HR for mortality increased as a function of follow-up time (5 to <10 years, HR 1.44, 95% CI 0.74–2.79; 10 to <15 years, HR 1.88, 95% CI 0.81–4.36). Having a CD diagnosis for ≥15 years was associated with a 2.80-fold increased risk of death in individuals with T1D (95% CI 1.28–6.12).

Conclusion

A diagnosis of CD for ≥15 years increases the risk of death in patients with T1D.


Abbreviations
T1D

type 1 diabetes

CD

coeliac disease

CI

confidence interval

HR

hazard ratio

aHR

adjusted hazard ratio

GFD

gluten-free diet

VA

villous atrophy

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

Coeliac disease (CD) is an immune-mediated enteropathy that affects about 1% of the population of Western countries. This complex chronic inflammatory disorder is associated with several autoimmune disorders, including type 1 diabetes (T1D) [1]. The prevalence of CD in individuals with T1D varies between 3% and 12% [2, 3].

Although treatment and management of T1D has improved over the years, patients with this disease are still at increased risk of death [4-7]. Two of the main causes of death in these patients are vascular disease and cancer [8]. An increased mortality risk in patients with CD has been reported by us [9] and others [10], in whom cardiovascular disease and cancer were the most frequent causes of death.

Concomitant CD may have a negative effect on some complications of diabetes in patients with T1D, including diabetic retinopathy [11, 12]. However, it is still unknown whether CD influences the mortality rate in patients with T1D. The aim of this population-based study was to examine the risk of death in 960 patients with both T1D and biopsy-proved CD compared with 4608 matched individuals with T1D alone (reference group). We hypothesized that CD confers an increased risk of death in patients with T1D.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

We estimated mortality in patients with both T1D and CD by linking data from the Swedish National Patient Register, Total Population Register and Cause of Death Register with nationwide histopathology data on CD.

This project (2011/841-31/3) was approved on June 15, 2011 by the Ethics Review Board, Stockholm, Sweden.

Type 1 diabetes

We identified individuals with a diagnosis of T1D in the Swedish National Patient Register [13] between 1964 and 2009 according to the appropriate International Classification of Diseases (ICD) codes [7th revision (ICD-7) 260, 8th revision (ICD-8) 250, 9th revision (ICD-9) 250 and 10th revision (ICD-10) E10). In Sweden, ICD-7, ICD-8 and ICD-9 codes did not distinguish between T1D and type 2 diabetes (T2D). In accordance with previous studies [14], we therefore defined T1D as a diagnosis of diabetes at ≤30 years of age. Early-onset T2D is still uncommon in Sweden [15], which further supports our definition of T1D based on age.

Coeliac disease

We obtained biopsy reports between 2006 and 2008 from all pathology departments in Sweden (28 departments) [9]. The biopsies were performed between 1969 and 2008, and CD was defined as duodenal/jejunal villous atrophy (VA; Marsh stage 3) [16]. Data were obtained for 29 096 individuals with biopsy-verified CD. VA has a high specificity for CD; according to earlier validation of the CD dataset used in this study, 95% of individuals with VA have CD [17].

Mortality data

Data on overall mortality were obtained from the Swedish Total Population Register, and cause-specific mortality data were obtained from the Swedish Cause of Death Register. In 2006, the National Board of Health and Welfare received death certificates for 99.3% of all deaths in Sweden [18]. The National Board of Health and Welfare identified 42 806 individuals with a diagnosis of T1D, and the government agency Statistics Sweden confirmed the identity of 42 578 (99.5%) of these individuals. Thirty-nine subjects were excluded because of data irregularities. Of the remaining 42 539 individuals with T1D, 960 (2.3%) had a diagnosis of CD before December 31, 2009. From the 41 579 individuals with T1D without a record of CD, we selected 4608 (five per CD/T1D case), matched for sex, age and calendar period of diagnosis, as the reference group.

Thus, this study was based on data from 960 individuals with both T1D and CD, and 4608 reference subjects with T1D alone.

Statistical analyses

We used Cox regression analysis with CD modelled as a time-dependent covariate to estimate mortality in individuals with T1D and CD, compared with those with T1D alone. In this model, data were stratified according to sex, age and calendar period at T1D diagnosis. Such an approach was used to eliminate the influence of the matching variables on the primary outcome variable, death. Follow-up began on the date of first T1D diagnosis and continued until death, emigration or the end of the study period (December 31, 2009), whichever occurred first.

We evaluated overall mortality based on years since CD diagnosis (<5 years, 5 to <10 years, 10 to <15 years and ≥15 years) (Table 2). Incidence rates were calculated by dividing the number of deaths by the number of person-years at risk. In a separate analysis, we adjusted for country of birth because the prevalence of CD [19] and T1D [20] varies in different parts of the world.

Table 1. Characteristics of the study participants
 Type 1 diabetes and coeliac diseaseType 1 diabetes alone
  1. Age was rounded to the nearest year.

  2. a

    Follow-up time until death, emigration or December 31, 2009, whichever occurred first.

  3. b

    Nordic country of birth.

Number of participants9604608
Age at T1D diagnosis, years, median (range)9 (0–30) 9 (0–30)
Age at T1D diagnosis, n (%)
Age 0–9 years566 (59.0)2655 (57.6)
Age 10–19 years261 (27.2)1294 (28.1)
Age 20–30 years133 (13.9)659 (14.3)
Age at end of study, years, median (range)22 (4–71) 22 (2–71)
Entry year (median, range)1994 (1996, 1964–2009)1994 (1997, 1964–2009)
Follow-upa, years, median (range)13 (0–46)12 (0–46)
Age at CD diagnosis, years, median (range)12 (1–63)
Women, n (%)528 (55.0)2515 (54.6)
Men, n (%)432 (45.0)2093 (45.4)
Calendar year, n (%)
1964–1975102 (10.6)482 (10.5)
1976–1987153 (15.9)746 (16.2)
1988–1999345 (35.9)1607 (34.9)
2000–2009360 (37.5)1773 (38.5)
Country of birthb, n (%) 952 (99.2)4470 (97.0)
Gestational diabetes, n (%)15 (1.6)93 (2.0)
Oral antidiabetic medication, n (%)19 (2.0)139 (3.0)
Table 2. Risk of death in type 1 diabetes and coeliac disease in relation to time since coeliac disease diagnosis
Follow-up, yearsObserved events Expected eventsaHR (95% CI)Absolute risk/100 000 PYARExcess risk/100 000 PYAR
  1. aHR, adjusted hazard ratio (for sex, age and calendar period at diagnosis of diabetes); CI, confidence interval; PYAR, person-years at risk. Reference group comprises individuals with type 1 diabetes without coeliac disease.

<510110.87 (0.43–1.73)249−37
5 to <1014101.44 (0.74–2.79)545167
10 to <15841.88 (0.81–4.36)625293
≥151042.80 (1.28–6.12)1212779

All-cause mortality was also evaluated in predefined subgroups, according to sex, and calendar year (1964–1975, 1976–1987, 1988–1999 and 2000–2009) and age at T1D diagnosis (0–9, 10–19 and 20–30 years) (Table 3). These age groups were selected because the onset of puberty in Swedish children is rarely before 10 years of age [21].

Table 3. Subgroup analyses: effect of coeliac disease on risk of death in patients with type 1 diabetes
SubgroupObserved eventsaHR (95% CI) Absolute risk/100 000 PYARExcess risk/100 000 PYAR
  1. aHR, adjusted hazard ratio (for sex, age and calendar period at diagnosis of diabetes); CD, coeliac disease; CI, confidence interval; PYAR, person-years at risk.

  2. a

    aHR could not be calculated because of too few events in this category.

0–9 years after CD diagnosis
Overall241.35 (0.88–2.07)36595
Sex
Male161.73 (1.02–2.94)545230
Female80.89 (0.43–1.85)220−27
Age at T1D diagnosis, years
0–931.14 (0.34–3.77)739
10–1961.22 (0.52–2.84)38069
20–30151.53 (0.89–2.65)1663576
Calendar period
1964–1975151.41 (0.82–2.42)1838534
1976–198751.41 (0.56–3.55)388113
1988–199931.22 (0.37–4.07)11020
2000–200911.29 (0.16–10.6)5813
≥10 years after CD diagnosis
Overall 182.08 (1.27–3.42)856444
Sex
Male112.95 (1.54–5.63)1412933
Female71.46 (0.67–3.18)529167
Age at TID diagnosis, years
0–9 21.18 (0.26–5.23)19229
10–19 94.34 (2.09–9.02)13681053
20–30 71.27 (0.58–2.77)1728367
Calendar period
1964–197591.60 (0.80–3.22)2632987
1976–198783.49 (1.60–7.62)1170835
1988–19990Not calculateda  
2000–200916.07 (0.70–52.9)431360

Because the proportional hazards assumption was not fulfilled in this model, the analysis was stratified for time since CD diagnosis. All subgroup analyses were divided into two time strata: <10 years and ≥10 years since diagnosis of CD. In a separate analysis, we evaluated cause-specific deaths according to the following categories: cardiovascular disease, cancer and death from any cause (Table 5). Follow-up in this analysis started at T1D diagnosis and continued until death (due to the specific/any cause), emigration or end of the study period (December 31, 2009).

Table 4. Cause-specific death in patients with type 1 diabetes and coeliac disease by duration of coeliac disease
 aHR (95% CI)
CD duration <10 years CD duration ≥10 years
  1. aHR, adjusted hazard ratio (for sex and age at diagnosis of type 1 diabetes and calendar period); CD, coeliac disease.

  2. a

    aHR was not calculated in this group because of a lack of events.

Cardiovascular disease1.70 (0.71–4.07)2.22 (0.86–5.78)
Cancer1.29 (0.38–4.41)Not calculateda
Any cause1.27 (0.74–2.16)2.73 (1.52–4.89)

Three sensitivity analyses were also performed to increase the specificity of T1D (Table 4). First, using data from the Prescribed Drug Register [22], we excluded individuals with a record of use of oral antidiabetic medication (anatomical therapeutic chemical classification system codes A10B and A10X) because of the possibility of having T2D despite an ICD-10 code consistent with insulin-dependent diabetes (E10). Secondly, we used data from the Swedish Medical Birth Register [23] to exclude women who received their first diagnosis of T1D during pregnancy (0–9 months before delivery), to avoid the possibility of including those with gestational diabetes rather than T1D. In the third subanalysis, we restricted study participants to those having an inpatient diagnosis of T1D (= 5391; 96.8%).

Table 5. Sensitivity analyses of the risk of death in patients with type 1 diabetes and coeliac disease
 aHR (95% CI)
CD duration <10 yearsCD duration ≥ 10 years
  1. aHR, adjusted hazard ratio (for sex, age and calendar period of diagnosis of diabetes); CD, coeliac disease; CI, confidence interval; T1D, type 1 diabetes (see text for definition).

First T1D diagnosis not during pregnancy1.37 (0.89–2.10)2.21 (1.34–3.63)
No oral antidiabetic medication1.25 (0.81–1.93)2.03 (1.24–3.33)
Inpatients with T1D1.35 (0.88–2.07)2.09 (1.27–3.42)

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

The median age at death was 45 (range 19–69) years in individuals with both T1D and CD, and 38 (range 2–67) years in the reference group (T1D alone). During a median follow-up period of 13 years, there were 42 (4.4%) deaths in individuals with both T1D and CD. The median follow-up time in control subjects was 12 years, and there were 223 (4.8%) deaths in this group. Characteristics of the study participants are shown in Table 1.

Overall mortality in relation to CD duration

Overall mortality risk correlated with duration of CD in patients with T1D. During the first 5 years after CD diagnosis, the risk of death was similar in individuals with both T1D and CD and in those with T1D alone [adjusted hazard ratio (aHR) 0.87; Table 2]. In the period from 5 to <10 years after CD diagnosis, the aHR increased (1.44) and continued to rise until 10 to <15 years after CD diagnosis (1.88; Table 2). The risk of death was even higher after 15 years of follow-up (aHR 2.80; Table 2).

The absolute risk of death was 249/100 000 person-years during the first 5 years following diagnosis of CD (Table 2). The absolute risk increased over time; 15 years after CD diagnosis, the absolute risk of death in patients with both T1D and CD was 1212/100 000 person-years, and the excess risk was 779/100 000 person-years (Table 2). Adjustment for country of birth did not change the risk estimates (data not shown).

Subgroup analyses

We found increasing aHRs of death in T1D patients with long-term exposure to CD in the subgroup analyses (Table 3). There was no interaction between CD and sex, age or calendar period at T1D diagnosis in these analyses. (Table 3).

Relation between cause-specific mortality and duration of CD

The aHRs for cardiovascular disease and death from any cause followed the same pattern of higher aHR more than 10 years after CD diagnosis (Table 4). The aHR for cancer death was 1.29 in the first 10 years after CD diagnosis, but because of lack of events thereafter, we were unable to calculate the aHR for cancer death in patients with T1D diagnosed with CD more than 10 years earlier.

Sensitivity analyses

The risk estimates did not change after excluding individuals with a record of oral antidiabetic medication or those who may have had gestational diabetes (T1D diagnosed 0–9 months before delivery); restriction of study participants to those with an inpatient diagnosis of T1D also had no effect on the results (Table 5).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

To our knowledge, this is the first population-based cohort study to examine both relative and absolute risks of death in patients with T1D and CD. The findings of this study suggest that long-term CD substantially increases mortality risk in patients with T1D.

This study has several strengths, including its population-based design and the independent ascertainment of cases from national health registers. The Swedish National Patient Register has been validated repeatedly, and the majority of diagnoses have a high positive predictive value (85–95%) [13]. Sensitivity for T1D is likely to approach 100% because hospital admission is mandatory at onset of T1D; in addition, a negative predictive value of diabetes of 100% was observed in patients admitted to hospital (= 872/872) in a Swedish validation study [24]. Data on pregnancy and antidiabetic medication enabled us to perform important sensitivity analyses (Table 5) to increase the specificity of T1D and to reduce the risk of misclassification.

Another strength is the ability to accurately define CD. Using nationwide data from small intestinal biopsies showing VA reduces the risk of selection bias because 96% of gastroenterologists and 100% of paediatricians in Sweden include a small intestinal biopsy in their diagnostic work-up for CD. In addition, VA is rarely explained by diagnoses other than CD (0.3% of individuals with VA had inflammatory bowel disease) [17]. Although positive CD serology was not included within the definition of CD, it has been demonstrated that 95% of individuals with VA have CD, and that 88% of those with available CD serology data have positive antibodies at the time of first biopsy [17].

Furthermore, the large number of study participants led to a high statistical power and enabled the calculation of important subanalyses, including stratified analyses according to sex, age and calendar period of CD diagnosis. The increased risk of death in T1D was found in both male and female patients with a long duration of CD, and there was no interaction between sex and CD with regards to T1D mortality. However, a short follow-up precluded the estimation of aHRs in the last calendar period. Nevertheless, the absolute risks decreased in the last calendar period (Table 3). This finding is to be expected, given that the majority of study participants were children and those who entered the study after 2000 did not reach adulthood (when mortality was highest) before the end of the follow-up period. Moreover, the median age of death in our study participants might seem low, but this is also to be expected as most of the participants were children at study entry.

A final study strength is that data from the Swedish Cause of Death Register allowed for the assessment of cause-specific mortality.

Some limitations of this study should also be considered. It has been reported that the prevalence of CD in patients with T1D is between 3% and 12% [1, 2, 25, 26]. At present, Swedish patients with T1D are screened for CD, but because such screening did not occur in the early part of our study period, we cannot rule out the possibility that some individuals classified as having T1D alone may also have undiagnosed CD. However, because individuals with T1D and undiagnosed CD would not make up more than 1–2% of our reference group [27], such misclassification would not affect our risk estimates more than marginally, and in any case would bias the aHR values towards 1. Another limitation of this study is the lack of data on smoking habits, haemoglobin A1c, body mass index, insulin therapy and gluten-free diet (GFD). However, smoking and obesity [28, 29] are associated with higher cardiovascular disease risk in T1D, whereas CD is inversely associated with both obesity [30] and smoking [31]. Thus, these factors are unlikely to explain our findings.

Individuals with T1D have an almost sevenfold higher risk of death compared with the general population [4]. During the first 10 years after T1D diagnosis, the major cause of death is acute diabetic complications (ketoacidosis and hypo/hyperglycaemia), whereas 10–20 years after T1D diagnosis, death is primarily due to chronic complications (e.g. cardiovascular disease, renal disease and infections) [7]. The findings of previous studies indicate that CD has an adverse effect on complications of T1D, including an increased risk of diabetic retinopathy [11, 12]. CD is associated with an increased risk of death (HR1.39) [9]. The most common cause of death in a large Swedish cohort was cardiovascular disease followed by cancer [9]. The underlying reason for the excess mortality seen in patients with CD has not yet been fully determined but may include malnutrition and chronic inflammation.

The lower risk of death observed during the first 5 years after CD diagnosis may be explained by a better adherence to a GFD or surveillance bias (frequent checkups soon after the diagnosis of CD). Another reason for the lower risk of death might be that patients with newly diagnosed CD have lower cholesterol levels compared with the general population [32].

Despite rapid clinical improvement in most patients with CD after starting a GFD, findings indicate that there is persistent low-grade inflammatory activity in the gut years after initiation of the diet [33, 34]. The explanation for the excess mortality demonstrated in this study in subjects with both T1D and CD could be persistent low-grade inflammation due to disease activity per se or poor adherence to a GFD. Adherence to a GFD is generally regarded as high in patients with CD and perhaps more so in individuals with a CD diagnosis early in life [35]. Although we have no data on the use of a GFD at the individual level in this study, adherence to such a diet was observed in 83% of a subset of our biopsy-verified patients with CD [17]. However, adherence to both a GFD and insulin therapy may differ [36]. If patients with T1D and CD find it difficult to follow a GFD, this lack of adherence may explain the excess mortality seen over time in those with both T1D and CD.

It has been shown that there is an increased risk of heart disease in CD [37], and low-grade inflammation has been suggested to trigger atherosclerosis [38]. An association between inflammation and atherosclerosis has further been supported by the finding in an Italian study of greater carotid intima–media thickness in patients with T1D and CD than in those with T1D alone, suggesting a higher degree of atherosclerosis progression in patients with both conditions [39].

We can only speculate about nonvascular and nonmalignant causes of death in T1D. Although there were more than 40 deaths in patients with T1D and CD, we did not have the statistical power to examine excess mortality for specific disorders. For example, CD is associated with a higher risk of end-stage renal disease (HR 2.87) [40], whereas T1D is the most common cause of this condition [41].

Recent findings from studies of the role of CD in metabolic control in patients with T1D are conflicting, but it seems that patients with both T1D and CD have lower height and weight gain compared with those with T1D alone [42, 43]. Poor nutritional status in patients with T1D and CD may also have contributed to the excess mortality observed in this study. However, the lack of data on metabolic control and the degree of adherence to a GFD are limitations of this study that should be addressed.

In conclusion, we have demonstrated an increased risk of death in patients with T1D and CD compared with patients with T1D alone. Based on these findings, we recommend close monitoring over time of patients with this combination of conditions (i.e. T1D and CD).

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

This project was supported by grants to JFL from The Swedish Society of Medicine, the Swedish Research Council – Medicine (522-2A09-195), the Sven Jerring Foundation, the Örebro Society of Medicine, the Karolinska Institutet, Örebro University Hospital, the Clas Groschinsky Foundation, the Juhlin Foundation, the Majblomman Foundation, Uppsala-Örebro Regional Research Council and the Swedish Celiac Society. The funding organizations had no role in the design or conduct of this study, including collection, management, analysis and interpretation of the data and preparation, review or approval of the manuscript.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References

KM and JFL are the guarantors of this work, had full access to all of the study data and take responsibility for data integrity and accuracy of the data analysis. KM designed the study, analysed the data and wrote the first draft of the manuscript; JFL designed the study and obtained funding. All authors contributed to the study design and interpretation of the data analyses; provided guidance on the development of statistical models; contributed to interpretation of the data; contributed to the writing of the manuscript, agree with the reported results and conclusions and met the criteria for authorship established by the CMJE

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  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest statement
  9. Author contributions
  10. References
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