Increased risk for inflammatory bowel disease in congenital hypothyroidism supports the existence of a shared susceptibility factor

Helmut Grasberger,Joyce M Lee,Mohamad El-Zaatari,Timothy D Kao,Akbar K Waljee,Jeremy Adler,Shrinivas Bishu,Mohamed Noureldin,John Y Kao

doi:10.1038/s41598-018-28586-5

Abstract

Loss-of-function mutations in dual oxidase (DUOX) 2 are the most common genetic variants found in congenital hypothyroidism (CH), and similar mutations have been recently reported in few very-early-onset inflammatory bowel disease (IBD) patients without CH. If DUOX2 variants indeed increase susceptibility for IBD, the enrichment of DUOX2 mutation carriers among CH patients should be reflected in higher risk for developing IBD. Using a database containing health insurance claims data for over 230 million patients in the United States, 42,922 subjects with CH were identified based on strict inclusion criteria using diagnostic codes. For subgroup analysis, CH patients with pharmacy records were stratified as transient or permanent CH based on the absence or presence of levothyroxine treatment, respectively. Patients were matched to an equal-sized, age- and gender-matched non-CH group. Compared to controls, CH patients had a 73% higher overall IBD prevalence (0.52% vs 0.30%; P < 0.0001). The CH-associated relative risk was higher for indeterminate or ulcerative colitis than Crohn’s disease. Patients with transient CH had higher odds for IBD (OR 2.39 (95% CI 1.77–3.23) than those with permanent CH (1.69 (95% CI 1.31–2.18). We conclude that patients with CH are at an increased risk of developing IBD. The risk was highest for patients with transient CH, for which partial defects in the DUOX2 system are a particularly common finding.

Highlights

The follicular cells of the thyroid gland constitutively express a homolog of the phagosomal NADPH oxidase, called dual oxidase 2 (DUOX2) that generates hydrogen peroxide at the apical membrane
There is no information from the published literature that any of the previously reported congenital hypothyroidism (CH) patients with DUOX2 mutations had GI symptoms, anecdotal support for the potential role of DUOX2 in inflammatory bowel diseases (IBD) pathogenesis has been recently provided by reports of DUOX2 loss-of-function mutations in children with IBD but not CH13–15
In light of these prior studies, the clear association between IBD risk and CH in the U.S population reported here is notable and would support the concept of a shared inborn susceptibility event, such as, variants in the DUOX2 system that are relevant for thyroid function as well as intestinal immune homeostasis

Summary

Introduction

The follicular cells of the thyroid gland constitutively express a homolog of the phagosomal NADPH oxidase, called dual oxidase 2 (DUOX2) that generates hydrogen peroxide at the apical membrane. Since a high proportion of patients identified in neonatal CH screening programs harbor DUOX2 variants that may contribute to the susceptibility for IBD, we hypothesized that the prevalence of IBD would be increased for a CH cohort compared to a matched non-CH cohort. To test this hypothesis, we performed a retrospective cohort analysis using a national payer database in the United States comprising individual-level health care claims data for 230 million individuals

Methods

Results

Conclusion