POPULATION STUDY ARTICLE Comorbidities in adolescents with inflammatory bowel disease: findings from a population-based cohort study Itai Ghersin 1,2 , Neron Khateeb 1 , Lior H. Katz 3 , Saleh Daher 1,3 , Raanan Shamir 4,5 and Amit Assa 4,5 BACKGROUND: Inflammatory bowel diseases are associated with various immune- and non-immune-mediated conditions. We aimed to assess the association of inflammatory bowel diseases with comorbidities at late adolescence. METHODS: Jewish Israeli adolescents who underwent a general health evaluation prior to enlistment to the Israeli Defense Forces from 2002 to 2016 were included. RESULTS: Overall, 891 subjects (595 Crohn’s disease, 296 ulcerative colitis, median age 17.1 years) and 1,141,841 controls were analyzed. Crohn’s disease was associated with arthritis (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.4–9.1), thyroid disease (OR 2.6, 95% CI 1.2–5.5), atopic dermatitis (OR 2, 95% CI 1.1–3.6), autoimmune hepatitis (OR 4.4, 95% CI 2.3–8.6), nephrolithiasis (OR 3.6, 95% CI 1.2–11.4), and pancreatitis (OR 41.8, 95% CI 17.2–101.9). Ulcerative colitis was associated with arthritis (OR 3.6, 95% CI 1.0–9.8), thyroid disease (OR 4.8, 95% CI 1.2–19.4), autoimmune hepatitis (OR 8, 95% CI 4–16.2), and pancreatitis (OR 51, 95% CI 16.1–158.9). Primary sclerosing cholangitis was associated with both diseases. Asthma, celiac, type 1 diabetes, psoriasis, and bone fractures were not more common in both diseases. Male predominance was noted for most associations. CONCLUSIONS: At adolescence, both Crohn’s disease and ulcerative colitis are associated with multiple comorbidities, not limited to autoimmune disorders. Pediatric Research (2020) 87:1256–1262; https://doi.org/10.1038/s41390-019-0702-3 INTRODUCTION Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are associated with a variety of chronic comorbidities. Its strongest and most studied associations are with other immune-mediated inflammatory diseases, plausibly through shared pathogenic pathways. 1 Immune-mediated diseases that were reported to be more common among patients with IBD include rheumatoid arthritis, 2,3 systemic lupus erythematosus, 2 hypothyroidism, 2 type 1 diabetes, 2 psoriasis, 3 asthma, 3–5 pernicious anemia, 5 and celiac disease. 6 Malabsorption, in addition to prolonged steroid use and inflammation-induced bone loss, also puts patients with IBD at increased risk of osteoporosis 7 and subsequent fractures’ risk. While not as well studied as the described association with other immune-mediated conditions, evidence suggests that IBD is also associated with non-immune-mediated conditions, such as increased risk for nephrolithiasis, 8 venous thromboembolism, 9,10 non-alcoholic fatty liver disease, 11 migraines, 12 and even Parkin- son’s disease. 13 The true prevalence of medical conditions associated with IBD is still obscured by limited data, which are mainly derived from relatively small cohorts. 12 Moreover, most studies of comorbidities in IBD examined adult patients, and specific data among children and adolescents with IBD are scarce. 2 Thus the aim of our study was to investigate the association of IBD diagnosis with various comorbidities in a cross-sectional, population-based study of subjects diagnosed with IBD at late adolescence. MATERIALS AND METHODS Study population Jewish adolescents who were born from 1987 to 1999 underwent a pre-enlistment medical evaluation at median age 17.1 years (interquartile range (IQR) 16.7–17.3 years) from 2004 to 2016. Strictly religious women who were exempt from medical board examination were excluded. For subjects with chronic diseases, enlistment is voluntary, and as such, complete medical history was available only for those who volunteered for military service. Ascertainment of IBD cases IBD diagnosis was established and confirmed by a military medical recruitment board. Medical information, including IBD diagnosis, was retrieved from medical history documents provided by the subject’s family physician for each individual case (Fig. 1). The diagnosis of IBD also required a confirmation document signed by a gastroenterologist, which included endoscopic, radiologic, histologic, and laboratory results at diagnosis and during follow- up. The minimal requirements for diagnosis included complete ileo-colonoscopy with a histologic report and small bowel imaging study (magnetic resonance enterography, computerized tomo- graphic enterography, or a small bowel follow-through). Received: 18 July 2019 Revised: 25 October 2019 Accepted: 31 October 2019 Published online: 4 December 2019 1 Medical Corps, Israel Defense Forces, Sheba Medical Center, Military P.O. Box 02149, Ramat Gan, Israel; 2 Department of Internal Medicine B/H, Rambam Health Care Campus, 8 Ha’aliyah Street, 31096 Haifa, Israel; 3 Department of Gastroenterology, Hadassah Ein Kerem Medical Center, Kiryat Hadassah, POB 12000, 91120 Jerusalem, Israel; 4 The Sackler School of Medicine, Tel Aviv University, 35 Klatskin Street, 6997801 Tel Aviv, Israel and 5 Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children’s Medical Center, 14 Kaplan Street, 4920235 Petach-Tikva, Israel Correspondence: Amit Assa (dr.amit.assa@gmail.com) www.nature.com/pr © International Pediatric Research Foundation, Inc. 2019 1234567890();,: