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Letters to the Editor

3. Hinescu ME, Ardeleanu C, Gherghiceanu M et al. Interstitial Cajal-like cells in human gallbladder. J Mol Histol 2007;38:275–84. 4. Ahmadi O, Nicholson Mde L, Gould ML et al. Interstitial cells of Cajal are present in human extrahepatic bile ducts. J Gastroenterol Hepatol 2010;25:277–85. 5. Matyja A, Gil K, Pasternak A et al. Telocytes: new insight into the pathogenesis of gallstone disease. J Cell Mol Med 2013;20:1–9. 1 Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland; 2Department of Pathophysiology, Jagiellonian University Medical College, Krakow, Poland; 3Department of Histology, Jagiellonian University Medical College, Krakow, Poland; 4First Department of General, Oncological and Gastrointestinal Surgery, Jagiellonian University Medical College, Krakow, Poland. Correspondence: Artur Pasternak, MD, PhD, Department of Anatomy, Jagiellonian University Medical College, Kopernika 12, Krakow 31-034, Poland. E-mail: [email protected]

Stress as a Risk Factor for Inflammatory Bowel Disease: More Evidence From Our OEF/OIF Veterans? Tauseef Ali, MD1,2, Casey S. Prammanasudh, BA3, Jason M. Samuels, BS3 and Mohammad F. Madhoun, MD2,4 doi:10.1038/ajg.2013.416

To the Editor: With a growing number of veterans returning from military engagements abroad, a new focus is being placed upon the psychological effects of experiencing combat. Depression, post-traumatic stress disorder (PTSD), and other psychiatric diseases are common diagnoses in veterans of wars such as Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) (1). With a plausible link between psychological stress and inflammatory bowel disease (IBD) (2–4), we hypothesized that exposure to combat and the subsequent presence of psychiatric disorders is related to the development of IBD. More specifically, we expected that veterans of OEF and OIF (post-combat veterans) with IBD would have a higher prevalence of psychiatric disorders than either non-OEF/OIF deployed veterans The American Journal of GASTROENTEROLOGY

Table 1. Demographic information and prevalence of different types of psychiatric disorders among cases and controls OEF/OIF with IBD cases n

OEF/OIF without IBD control 1

Non-OEF/OIF with IBD control 2

202

426

6,808

32.6a±9.0

35.2±9.4

58.2a±14.7

28.2

29.4

28.6

Gender (% males)

177:26 (87%)

368:58 (86%)

6,358:449 (93%)

IBD type (CD/UC)

103/99 (51%/49%)

NA

3,127/3,681 (46%/54%)

4.5 ± 2.3 years. Range: 0.83-9.98

n/a

53 (26%) UC 63 (31%) CD

91 (21%)

2,518 (37%) UC 2,723 (40%) CD

Overall psychiatric disorders

50%

32% OR=1.76 95% CI 1.26, 2.48

36% OR=2.8 95% CI: 2.15, 2.79

Bipolar/manic disorder

3%

2% OR=1.41 95% CI: 0.50, 4.04

2.5% OR=1.15 95% CI: 0.50, 2.63

Major depressive/ mood disorder

11%

9% OR= 1.35 95% CI: 0.78, 2.34

10% OR=1.15 95% CI: 0.74, 1.78

Anxiety/panic disorder

28%

20% OR=1.53 95% CI: 1.04, 2.25

22% OR=1.41 95% CI: 1.04, 1.93

PTSD

32%

26% OR=1.31 95% CI: 0.91, 1.89

13% OR=3.03 95% CI: 2.27, 4.04

Mean age in years (at diagnosis) Mean BMI

Years to develop IBD after deployment (mean±s.d.) Smoking

BMI, body mass index; CD, Crohn’s Disease (ICD9 555.X); CI, confidence interval; IBD, inflammatory bowel disease; OEF, Operation Iraqi Freedom; OIF, Operation Enduring Freedom; OR, odds ratio; PTSD, post-traumatic stress disorder; UC, Ulcerative Colitis (ICD9 556.X). a Age at diagnosis.

(non-combat veterans) with IBD or postcombat veterans without IBD. In this pilot study, we used a two-to-one case–control analysis utilizing psychiatric and drug history data from the South Central VA Health Care Network VISN 16 medical database. The sample included data from 202 combat veterans with IBD (case group, ICD-9 codes 555-556-x) diagnosed between January 1996 and May 2012 following their initial deployment date, 426 non-matched randomly selected combat veterans without IBD (control group 1), and 6,808 veterans with IBD who were not deployed to OEF or OIF but developed IBD during the same time period (control

group 2) (Table 1). The psychiatric disorders studied were bipolar/manic disorders, major depression/mood disorders, anxiety/panic disorders, and PTSD. Odds ratios were used to quantify and compare risks between the case group and control groups. Data was excluded from analysis if the patient had an IBD diagnosis before the deployment, a psychiatric disorder diagnosed after the IBD diagnosis or before the deployment to OEF/OIF, or a diagnosis of non-infectious or non-specified colitis (ICD 558.x). We discovered that more post-combat veterans with IBD were diagnosed with psychiatric disorders when compared with postVOLUME 109 | APRIL 2014 www.amjgastro.com

Letters to the Editor

REFERENCES

OR=2.8; 95%Cl: 215, 2.79

Psychiatric disorders (%)

OR=1.76; 95% Cl: 1.26, 2.48 60 50 40 30 20 10 0 OEF/OIF with IBD

OEF/OIF without IBD

Non-OEF/OIF with IBD

Figure 1. Prevalence of overall psychiatric disorders among OEF/OIF veterans with and without IBD and non-OEF/OIF veterans with IBD. OEF, Operation Iraqi Freedom; OIF, Operation Enduring Freedom.

combat veterans without IBD (odds ratio (OR) 1.76; 95% confidence interval (CI) 1.26, 2.48) and non-combat veterans with IBD (OR 2.8; 95% CI 2.15, 2.79) (Figure 1). The different psychiatric disorders and their prevalence among case and control groups are described in Table 1. There was significantly higher prevalence of PTSD and anxiety/panic disorders among post-combat veterans. This suggests that the increase in psychiatric disorders in post-combat veterans with IBD is indiscriminate. Post-combat veterans with IBD also reported significantly greater utilization of IBD drug therapy, including steroid, immunomodulators and biologics use, compared with non-combat veterans with IBD (OR = 2.8; 95%CI: 2.15, 2.79). In conclusion, there may be an association between psychological stress related to combat experience and the development of psychiatric disorders with subsequent development of IBD. This phenomenon further supports a connection between environmental stressors (e.g., combat) and the development of IBD. At a certain threshold, stress could have manifested as psychiatric illness in the combat veterans and later on lead to the development of IBD in high-risk patient population. Several limitations exist within this study, including a degree of selection bias as well as failure to control for possible confounders including age. Only regional VA administrative database was analyzed. Future studies could attempt to address these limitations by using a larger, age-matched, more varied population of combat or non-combat veterans. Nevertheless, such a relation© 2014 by the American College of Gastroenterology

ship could have a number of implications on the management of returning veterans. If experiencing extremely stressful events does increase one’s risk for developing IBD, then there exists additional incentive to reduce and manage stress-induced psychiatric disorders early in the development of psychiatric disease in military personnel. Early intervention in veterans’ progression of psychiatric disease could potentially lead to the prevention or delay of IBD development. Future studies could look at the efficacy of such interventions in the treatment of IBD, and eventually lead to integration of psychiatric therapies into standards of care for IBD. Further research investigating the exact mechanistic connection between stress and IBD is also warranted. CONFLICT OF INTEREST

Guarantor of the article: Tauseef Ali, MD. Specific author contributions: Tauseef Ali: Study idea, design, analysis and final draft approval; Casey S. Prammanasudh: study design and analysis; Jason M. Samuels: study analysis and manuscript writing; Mohammad F. Madhoun, MD: study design, analysis and final draft approval. All authors have approved the final draft submitted. Financial support: None. Potential competing interests: None. DISCLAIMER

The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs..

1. Lane ME, Hourani LL, Bray RM et al. Prevalence of perceived stress and mental health indicators among reserve-component and active-duty military personnel. Am J Public Health 2012;102:1213–20. 2. Reber SO. Stress and animal models of inflammatory bowel disease--an update on the role of the hypothalamo-pituitary-adrenal axis. Psychoneuroendocrinology 2012;37: 1–19. 3. Maunder RG. Evidence that stress contributes to inflammatory bowel disease: evaluation, synthesis, and future directions. Inflamm Bowel Dis 2005;11:600–8. 4. Bernstein CN, Singh S, Graff LA et al. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol 2010;105:1994–2002.

1

OU Physicians Inflammatory Bowel Disease Center, Oklahoma City, Oklahoma, USA; 2Section of Digestive Diseases and Nutrition, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; 3Department of Internal Medicine, College of Medicine, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA; 4VA Medical Center, Oklahoma City, Oklahoma, USA. Correspondence: Tauseef Ali, MD, OU Physicians Inflammatory Bowel Disease Center, WP1345, 920 SL Young Blvd., Oklahoma City, Oklahoma, 73104, USA. E-mail: [email protected]

When the Dissolvable Does not Dissolve: An Agile Patency Capsule Mystery Amara Okoli, MD, MPH1, Nischala Ammannagari, MD1, Mohammed Mazumder, MD2 and Kiran Nakkala, MD, MPH2 doi:10.1038/ajg.2013.435

To the Editor: Capsule retention is the most frequent side effect of video capsule endoscopy (VCE). Its incidence is often dependent on the indication for VCE with rates of 1.2% reported for acute obscure gastrointestinal (GI) bleeding (1). Radiological screening for intestinal strictures before VCE have been largely inaccurate (2). Consequently, in patients with suggested risk of retention from history (Crohn’s disease, NSAID use, radiation to the abdomen/pelvis, small bowel The American Journal of GASTROENTEROLOGY

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