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Tissue Studies in Screened First-degree Relatives Reveal a Distinct Crohn's Disease Phenotype

Sorrentino, Dario MD*,†; Avellini, Claudio MD; Geraci, Marco PhD§; Dassopoulos, Themistocles MD; Zarifi, Dimitra MD*; Vadala' di Prampero, Salvatore Francesco MD*; Benevento, Gianluca MD*

doi: 10.1097/MIB.0000000000000051
Original Clinical Articles

Background: First-degree relatives of patients with Crohn's disease (CD) are at risk of developing the disease with 5% to 15% reported to be affected over time. Yet, a much greater proportion of them (>40%) shows features of “subclinical inflammation” with elevated intestinal inflammatory markers such as fecal calprotectin. The meaning of these findings is unclear in the absence of tissue data.

Methods: Thirty-eight asymptomatic first-degree relatives of patients with CD underwent ileocolonoscopy and other tests including fecal calprotectin. All known causes of intestinal inflammation were carefully excluded. Age and gender-matched controls consisted of 10 individuals who underwent colonoscopy for other reasons. Histology was scored based on known methods.

Results: Compared with controls, the relatives had significantly greater median values for fecal calprotectin and histological scores. In relatives, endoscopy identified 3 different phenotypes: (1) normal, (2) with minor lesions (aphthae or small superficial erosions), and (3) with typical CD inflammation. Based on the histological scores, the clustering analysis produced 3 corresponding highly separated clusters (61%, 26%, and 13% of the total, respectively) with divisive coefficient D = 0.94. When followed up (on the average for 53 mo), individuals in the second cluster had histological scores similar to baseline values (P = 0.12).

Conclusions: Tissue studies in first-degree relatives of patients with CD reveal 3 distinct groups: normal, with minimal inflammation, and with frank disease. The second cluster represents a novel phenotype, which does not seem to develop the disease over time. These findings explain previous observations of “subclinical inflammation” in such population.

Article first published online 30 April 2014.

*Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, Udine, Italy;

IBD Center, Division of Gastroenterology, Virginia Tech-Carilion School of Medicine, Roanoke, Virginia;

Department of Pathology, University of Udine School of Medicine, Udine, Italy;

§Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom; and

IBD Center, Division of Gastroenterology, Washington University in St. Louis, St. Louis, Missouri.

Reprints: Dario Sorrentino, MD, Division of Gastroenterology, Virginia Tech-Carilion School of Medicine, 3 Riverside Circle, Roanoke, VA 24016 (e-mail:

The authors have no conflicts of interest to disclose.

Received March 16, 2014

Accepted March 19, 2014

© Crohn's & Colitis Foundation of America, Inc.
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