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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*

Inflammatory Bowel Diseases:
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.

In Brief

Article first published online 30 April 2014.

Author Information

*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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