Type 1 Diabetes and Microscopic Colitis

A Nationwide Matched Case-control Study in Sweden

Xiaoying Kang; Shengxin Liu; Bjorn Roelstraete; Hamed Khalili; Jonas F. Ludvigsson

Aliment Pharmacol Ther. 2023;57(12):1423-1431.

Abstract and Introduction

Abstract

Background and Aims: Microscopic colitis (MC) is a colonic inflammatory condition associated with autoimmune dysfunction. Type 1 diabetes (T1D) is a chronic disease induced by autoimmune destruction of pancreatic β-cells. We aimed to examine the association between T1D and MC.

Methods: A matched case–control study was conducted using the nationwide ESPRESSO cohort as study base. All biopsy-confirmed MC patients born after 1940 were identified and compared to biopsy-free individuals matched from the general population for T1D diagnosis using the Swedish National Patient Register. The T1D-MC association was estimated as odds ratios (ORs) and 95% confidence intervals (CIs) by conditional logistic models, considering differences by sex and MC subtype. Full sibling comparison and adjustment for MC-associated medications were also performed.

Results: We identified 352 (3.7%) and 945 (2.0%) T1D diagnoses from 9,600 MC cases and 47,870 matched population controls, respectively, which corresponded to an overall OR of 1.79 (95% CI: 1.56–2.05). The association was stronger for collagenous colitis (OR, 2.15; 95% CI: 1.70–2.71) than lymphocytic colitis (OR, 1.62; 95% CI: 1.37–1.92) and remained statistically significant in full sibling comparison (OR, 1.46; 95%: 1.18–1.81). Medication adjustment attenuated the association to null among females (OR: 1.02; 95% CI: 0.82–1.27) but not among males (OR: 1.45; 95% CI: 1.11–1.90).

Conclusion: T1D diagnosis was almost 80% more prevalent in MC patients compared to general population. This positive association did not seem to be spurious due to residual confounding shared by full siblings but may relate to consumption of medications associated with MC onset.

Introduction

Comprising lymphocytic colitis and collagenous colitis as two major subtypes, microscopic colitis (MC) is a chronic inflammatory condition of the colon manifested by watery diarrhoea.^[1] Although the aetiology of MC remains poorly understood, a growing number of risk factors, including a handful of drugs that may induce the onset of MC, and underlying mechanisms have been elucidated.^[2–4] Among these, autoimmune dysfunction has been robustly connected to MC by the mounting evidence associating MC with various autoimmune comorbidities.^[5–7]

Affecting mainly children and young adults, type 1 diabetes (T1D) is induced by the autoimmune-mediated destruction of pancreatic β-cells and the resulted insulin deficiency.^[8] Diarrhoea is also more commonly experienced by diabetic patients.^[9,10] By comparing the population-based MC patients to their matched controls for concomitant autoimmune diseases, a Danish study recently observed a 35% higher prevalence of T1D in relation to MC, corroborating an earlier Swedish study of smaller sample as well as the accumulating experimental data supporting a shared pathophysiology (i.e. gut dysbiosis, disruption of intestinal permeability, and dysregulation of mucosal immunity) between MC and T1D.^[6,7,11,12]

Therefore, the present study aimed to interrogate the specific relation between T1D and MC by harnessing the national register data in Sweden.

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Next Section

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Characteristics of patients with microscopic colitis (cases) and their matched population controls.
	MC cases			Population controls
	Combined	CC	LC	Population controls
Total	9600 (100)	2849 (100)	6751(100)	47,870 (100)
Age at index date	51.9 (14.3)	54.7 (12.3)	50.7 (14.9)	51.9 (14.3)
Females	6966 (72.6)	2220 (77.9)	4746 (70.3)	34,756 (72.6)
Born in Sweden	8924 (93.0)	2722 (95.5)	6202 (91.9)	41,537 (86.8)
Type 1 diabetes
Lifetime diagnosis	352 (3.7)	138 (4.8)	214 (3.2)	945 (2.0)
Pre-index diagnosis	279 (2.9)	115 (4.0)	164 (2.4)	675 (1.4)
Year of index date
1991–2005	2115 (22.0)	628 (22.0)	1487 (22.0)	10,540 (22.0)
2006–2017^a	7485 (78.0)	2221 (78.0)	5264 (78.0)	37,330 (78.0)
Year of birth
1940–1959	6168 (64.3)	2075 (72.8)	4093 (60.6)	30,744 (64.2)
1960–1979	2587 (27.0)	653 (22.9)	1934 (28.7)	12,901 (27.0)
After 1980	845 (8.8)	121 (4.3)	724 (10.8)	4225 (8.8)
Pre-index status of comorbidities
Celiac disease	473 (4.9)	139 (4.9)	334 (5.0)	32 (0.1)
IBD	676 (7.0)	205 (7.2)	471 (7.0)	201 (0.4)
Asthma	717 (7.5)	199 (7.0)	518 (7.7)	2198 (4.6)
Other AIDs^b	1247 (13.0)	456 (16.0)	791 (11.7)	2983 (6.2)
Years of education
≤9	1634 (17.0)	561 (19.7)	1073 (15.9)	8800 (18.4)
10–12	4260 (44.4)	1333 (46.8)	2927 (43.4)	20,881 (43.6)
≥13	3621 (37.7)	941 (33)	2680 (39.7)	17,505 (36.6)
Missing	85 (0.9)	14 (0.5)	71 (1.1)	684 (1.4)

Note: Values are mean (standard deviation) for "Age at index date" and N (%) for other variables.
Abbreviations: AIDs, autoimmune disorders; CC, collagenous colitis; IBD, inflammatory bowel disease; LC, lymphocytic colitis; MC, microscopic colitis.
^aSub-sample analysed in the medication-adjusted models.
^bIndicating the pre-index diagnosis of any one among thyroiditis, hyperthyroidism, psoriasis, or rheumatoid arthritis.

Table 2. Characteristics of patients with microscopic colitis (cases) and their full siblings.
	MC cases	Full sibling controls
Total	6594 (100)	12,798 (100)
Age at index date	50.9 (14.5)	50.9 (14.0)
Females	4790 (72.6)	6306 (49.3)
Born in Sweden	6507 (98.7)	12,594 (98.4)
Type 1 diabetes
Lifetime diagnosis	241 (3.7)	322 (2.5)
Pre-index diagnosis	198 (3.0)	257 (2.0)
Year of index date
1991–2005	1427 (21.6)	2762 (21.6)
2006–2017	5167 (78.4)	10,036 (78.4)
Year of birth
1940–1959	4055 (61.5)	7955 (62.2)
1960–1979	1885 (28.6)	3657 (28.6)
After 1980	654 (9.9)	1186 (9.2)
Pre-index status of comorbidities
Celiac disease	353 (5.4)	106 (0.8)
IBD	470 (7.1)	306 (2.4)
Asthma	477 (7.2)	686 (5.4)
Other AIDs^a	840 (12.7)	886 (6.9)
Years of education
≤9	1018 (15.4)	2553 (20.0)
10–12	2926 (44.4)	5717 (44.7)
≥13	2607 (39.5)	4088 (31.9)
Missing	43 (0.7)	440 (3.4)

Note: Values are mean (standard deviation) for "Age at index date" and N (%) for other variables.
Abbreviations: AIDs, autoimmune disorders; IBD, inflammatory bowel disease; MC, microscopic colitis; T1D, type 1 diabetes.
^aIndicating the pre-index diagnosis of any one among thyroiditis, hyperthyroidism, psoriasis, or rheumatoid arthritis.

Table 3. Odds ratios and 95% confidence intervals of associations between pre-index diagnosis of type 1 diabetes and microscopic colitis.
	Population controls^a	Sibling controls^b
Overall	1.98 (1.7, 2.31)	1.50 (1.18, 1.90)
By sex
Males	2.21 (1.72, 2.84)	1.79 (1.09, 2.94)
Females	1.86 (1.53, 2.26)	1.47 (1.02, 2.13)
By disease subtype
Collagenous colitis	2.49 (1.92, 3.22)	1.91 (1.32, 2.75)
Lymphocytic colitis	1.74 (1.44, 2.11)	1.28 (0.93, 1.77)

^aMain analysis comparing cases of microscopic colitis to their matched population controls, adjusted for birth country, education, and pre-index diagnosis of celiac disease, inflammatory bowel disease, asthma, and other autoimmune disorders.
^bSensitivity analysis comparing cases of microscopic colitis to their biopsy-free siblings, adjusted for sex, age at index date, birth country, education, and pre-index diagnosis of celiac disease, inflammatory bowel disease, asthma and other autoimmune disorders, and conditioned on family-cluster.

Table 4. Dispensation of selected medications between individuals with and without type 1 diabetes in the subsample with index date ≥2006-01-01.
	Females		Males
	With T1D	Without T1D	With T1D	Without T1D
Total	624 (100)	32,023 (100)	356 (100)	11,812 (100)
Age at index date	57.7 (12.5)	52.9 (1.43)	60.5 (11.0)	53.8 (15.0)
Microscopic colitis	176 (28.2)	5275 (16.5)	102 (28.7)	1932 (16.4)
Dispensation of selected medications
Statin	439 (70.4)	3159 (22.4)	268 (75.3)	3282 (27.8)
SSRI	323 (51.8)	10,400 (32.5)	146 (41.0)	3215 (27.2)
PPI	189 (30.3)	6220 (19.4)	60 (16.9)	1349 (11.4)
NSAIDs	423 (67.8)	16,773 (52.4)	245 (68.8)	5997 (50.8)

Note: Values are mean (standard deviation) for "Age at index date" and N (%) for other variables.
Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitors; SSRI, selective serotonin reuptake inhibitors; T1D, type 1 diabetes.

Table 5. Odds ratios and 95% confidence intervals of association between type 1 diabetes and microscopic colitis, after adjusting for selected medication.
	All-adjusted	Statin adjusted	PPI adjusted	SSRI adjusted	NSAIDs adjusted
Overall	1.16 (0.98, 1.37)	1.22 (1.04, 1.44)	1.77 (1.51, 2.07)	1.84 (1.57, 2.15)	1.87 (1.61, 2.18)
By disease subtype
Collagenous colitis	1.47 (1.09, 1.96)	1.44 (1.10, 1.88)	2.31 (1.77, 3.03)	2.35 (1.79, 3.08)	2.28 (1.76, 2.95)
Lymphocytic colitis	1.00 (0.82, 1.24)	1.11 (0.91, 1.35)	1.52 (1.25, 1.85)	1.59 (1.31, 1.94)	1.66 (1.37, 2.01)
By sex
Males	1.45 (1.11, 1.90)	1.44 (1.11, 1.87)	1.99 (1.54, 2.58)	2.06 (1.59, 2.66)	2.02 (1.57, 2.61)
Females	1.02 (0.82, 1.27)	1.12 (0.92, 1.37)	1.66 (1.36, 2.03)	1.72 (1.41, 2.1)	1.79 (1.48, 2.17)

Note: Results are estimated from conditional logistic models comparing microscopic colitis patients diagnosed after 2006–01-01 to their matched population controls, adjusting for birth country, education, pre-index diagnosis of seven comorbidities, and corresponding medications prescribed within 6 months before index date.
Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitor; SSRI, selective serotonin reuptake inhibitor.