Crohn s disease (CD) is a chronic inflammatory bowel disease. Ratio of Visceral to Subcutaneous Fat Area Is a Biomarker of Complicated Crohn s Disease

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9: Ratio of Visceral to Subcutaneous Fat Area Is a Biomarker of Complicated Crohn s Disease BARA ERHAYIEM,* RAJPAL DHINGSA, CHRISTOPHER J. HAWKEY,* and VENKATARAMAN SUBRAMANIAN* *Nottingham Digestive Diseases Centre and Department of Radiology, Nottingham University Hospital, Nottingham, United Kingdom BACKGROUND & AIMS: Fat wrapping and mesenteric hypertrophy are characteristics of Crohn s disease (CD). In patients with CD, mesenteric adipose tissue releases higher levels of adiponectin, which could up-regulate production of tumor necrosis factor- and increase the risk for aggressive disease. We investigated whether a higher ratio of visceral to subcutaneous fat was associated with complicated (fistulating or stricturing) CD. METHODS: We identified patients with a confirmed diagnosis of CD who had computed tomography scans of their abdomens (n 50). Areas of subcutaneous and visceral fat were measured in 1 cross-sectional scan that was taken at the level of the umbilicus. The mesenteric fat index (MFI), defined as the ratio of areas of visceral to subcutaneous fat, was compared between patients with complicated (strictures and fistulas) and inflammatory CD. RESULTS: The mean age of the patients with complications (n 29) was years, and in patients with inflammatory CD (n 21) it was years. The MFI was significantly higher (P.001) in patients with complicated disease ( ) than in those with uncomplicated disease ( ) and was the only variable that remained significantly different on multivariate analysis. The area under the receiver operating curve for the MFI was 0.95 (95% confidence interval, ), and an MFI of 0.29 identified patients with complicated CD with 93% sensitivity and 81% specificity. CONCLUSIONS: A high ratio of areas of visceral to subcutaneous fat (MFI) is a marker of aggressive CD. Further studies are needed to determine the roles of adipose tissue in pathogenesis of CD. Keywords: IBD; Prognosis; CT Imaging; TNF. Crohn s disease (CD) is a chronic inflammatory bowel disease (IBD) that involves the entire gastrointestinal tract. Its etiology is still unknown, and CD is diagnosed by a combination of clinical, endoscopic, radiologic, and histologic characteristics. Changes in the mesenteric fat in CD have been widely recognized since its first description in 1932 by Dr Burril B. Crohn. 1 Accumulation of mesenteric fat with fat wrapping is fairly common in CD and is known to occur from the onset of the disease. 2 The relevance of this finding has often been debated, but surgical series have shown that mesenteric fat hypertrophy and fat wrapping occur in both the small and large bowel and is correlated with ulceration, stricture formation, transmural inflammation, wall thickness, and internal bowel diameter. 3 There is still controversy on whether fat hypertrophy and fat wrapping are primary or secondary phenomena in patients with CD. 4 Fat wrapping could be a result of transmural inflammation with release of proinflammatory cytokines like tumor necrosis factor- (TNF- ) and transforming growth factor- from the intestinal mucosa and macrophages in adjacent soft tissue, promoting activation of peroxisome proliferatoractivating receptor-, which in turn promotes adipose tissue hypertrophy. 5,6 Increasingly, however, there seems to be some evidence that mesenteric adipose tissue might play a more active role in the pathogenesis of CD. 4,7 Mesenteric adipocytes in CD have been shown to secrete both proinflammatory mediators like TNF- 2 and anti-inflammatory cytokines like interleukin Leptin mrna expression has also been shown to be higher in mesenteric fat from CD patients. Leptin can induce intestinal inflammation and could contribute to the increased TNF- overexpression in these patients. The release of adiponectin from mesenteric adipose tissue, a potent anti-inflammatory cytokine, is also increased in patients with CD and is found specially related to inflamed and hypertrophied tissue. Mesenteric fat hypertrophy in CD might be both a cause and a consequence of inflammation. Its relevance to the clinical course of CD is less well-studied. Computed tomography (CT) and magnetic resonance imaging have both been shown to provide an accurate assessment of intra-abdominal fat by measuring the visceral fat area and subcutaneous fat area in the same section. 9,10 Cytokine production profiles differ between subcutaneous and visceral fat, 11 and this could explain why obesity-associated metabolic disorders correlate positively with visceral fat area and not subcutaneous fat area. 12 The association between visceral fat and complicated CD has not been previously studied. This retrospective cohort study looked at whether a higher visceral to subcutaneous fat ratio was associated with a greater risk of developing complicated CD (defined as those with strictures or fistulas). Methods Patients We identified patients with a confirmed diagnosis of CD from our IBD database and selected patients who had had CT scans of their abdomen between April 2007 and November In all cases the diagnosis of CD was confirmed by a combination of clinical, endoscopic, histologic, or radiologic findings. Details of the dates of the scans were obtained from the electronic patient records of the Nottingham University Hospital. Digitally archived scans were then retrieved from the picture archiving and communication systems (IMPAX system; Abbreviations used in this paper: CD, Crohn s disease; CT, computed tomography; IBD, inflammatory bowel disease; MFI, mesenteric fat index; TNF-, tumor necrosis factor by the AGA Institute /$36.00 doi: /j.cgh

2 August 2011 MESENTERIC FAT IN CROHN S DISEASE 685 Agfa-Gevaert N.V., Belgium) at the Nottingham University Hospital. Demographic details of the patients, medication use, smoking status, disease locations, and duration of disease were then obtained from the electronic patient records and from the case notes by a researcher blinded to the CT measurements (V.S.). Measurements and Analysis Visceral and subcutaneous fat areas were measured retrospectively on the CT scans performed previously described at the level of the umbilicus (around L4 vertebral level) with the patient in the supine position. 10,13 Briefly, Adobe CS3 with Photoshop Magic Wand (Adobe Systems, San Jose, CA) was used to outline and measure the subcutaneous and visceral fat areas in each of the stored digital images as previously described. 10,13 The visceral and mesenteric fat areas were measured in square centimeters on the basis of the pixel count. The mesenteric fat index (MFI), defined as a ratio of visceral to subcutaneous fat area, was calculated for each patient. The CT measurements were done by a researcher (B.E.) blinded to the clinical data. The MFI was compared between patients with complicated CD (strictures and fistulas or those classed as B2 or B3 on the Montreal IBD classification) and inflammatory CD (those classed as B1 on the Montreal IBD classification). 14 Statistical analysis was done by using SPSS v17 (SPSS, Inc, Chicago, IL). In patients with more than 1 CT scan, the average measurements were used. Results Fifty patients (72 scans) with CD were included (21 with inflammatory CD and 29 with complicated CD). The clinical details of the patients are shown in Table 1. Patients with complicated CD (B2 or B3) were slightly older than those with inflammatory disease (B1). The groups were well-matched for gender and disease location, and numbers with elevated C-reactive protein levels ( 8 ng/ml) were not significantly different between the 2 groups. Table 1. Clinical Details of Patients With CD Complicated CD Inflammatory CD No. of patients Mean age (y SD) a Mean duration (y SD) b Mean age at diagnosis (y SD) Gender (male/female) c 17/12 5/16 Location of disease L2/L3 d 25/4 14/7 Behavior e B1: 21 CRP (ng/l) (elevated/normal) 21/8 13/8 Smoking (yes/no) 12/17 9/12 Immunomodulator or biological use (yes/no) 10/11 13/16 CRP, C-reactive protein; SD, standard deviation. a P.03. b P.04. c P.02. d L2: ileal and L3: colonic (Montreal classification). e B1, nonstricturing, nonpenetrating; B2, stricturing; B3, penetrating (Montreal classification). Table 2. MFI and Visceral and Subcutaneous Fat Area in Complicated and Inflammatory CD Complicated Inflammatory P value All patients (n 50) MFI Visceral fat Subcutaneous fat Female patients (n 28) MFI Visceral fat Subcutaneous fat Male patients (n 22) MFI Visceral fat Subcutaneous fat NOTE. All data presented as mean standard deviation. Computed Tomography Measurements The mean subcutaneous and visceral fat area and MFI of the 2 groups are shown in Table 2. The MFI was significantly higher in patients with complicated CD. On multivariate analysis adjusting for age, sex, duration of disease, visceral fat area (all factors significant on univariate analysis), only the MFI was significantly different between complicated and uncomplicated CD (Table 3). Figure 1 shows the MFI according to disease behavior (inflammatory, stricturing, penetrating, or both). Age was a significant factor only on univariate analysis, but not on multivariate analysis, and Figure 2 shows a scatterplot of the MFI according to age and duration of disease, with a normal distribution noted for both complicated and inflammatory disease behavior. The area under the receiver operating characteristic curve for the MFI in identifying patients with complicated CD was 0.95 (95% confidence interval, ). The receiver operating characteristic curve is illustrated in Supplementary Figure 1. A cutoff of 0.29 for the MFI was 93.7% sensitive and 81% specific for detecting complicated disease behavior. Discussion CD patients with higher body mass index have been shown to require earlier surgical interventions and higher rates Table 3. Multivariate Analysis for Predictors of Complicated Behavior in Patients With CD Factor P value (univariate) P value (multivariate) Sex Duration of disease Age Visceral fat area MFI

3 686 ERHAYIEM ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 8 Figure 1. Mean MFI according to disease behavior. CI, confidence interval. of anoperineal complications. 15,16 The mechanisms underlying the association between obesity and complicated CD are unknown, but it is postulated to be an increased cytokine cascade that is caused by peroxisome proliferator-activated receptor overexpression in the intra-abdominal fat, which might sustain the inflammatory response in obese CD patients. 2 However, there is controversy on the definition of obesity, and several studies now suggest that waist circumference or waist-hip ratio might be better predictors of disease than body mass index. 17 These external measures are crude estimates of body fat distribution and fail to distinguish between visceral and subcutaneous fat. CT can reliably estimate visceral and subcutaneous fat area from a single scan obtained at the level of the umbilicus (approximately the level of L4 and L5), and these are highly correlated with the total body fat. 9,10,13 This study showed that visceral fat area is highly correlated with development of complicated CD (stricture or fistula), and a higher visceral to subcutaneous fat ratio (MFI) can predict a more complicated course of the disease. Visceral fat accumulation has also been shown to be associated with the development of colorectal adenoma and colon cancer, 18 and the amount of visceral fat predicts disease-free survival in patients with resectable colon cancer. 19 Intra-abdominal fat wrapping (hyperplasia of visceral fat) is common in CD patients undergoing resectional surgery. Fat wrapping was identified in 12 of 16 ileal resections and 7 of 11 colonic resections from an unselected surgical series, and this correlated with other connective tissue changes including fibrosis, muscular hypertrophy, and stricture formation. 3 A French study with magnetic resonance imaging showed that visceral fat to subcutaneous fat area was significantly higher in CD patients compared with healthy controls, but the distribution of fat did not correlate with CD activity index, duration of disease, or steroid use. 2 Occurrence of excessive visceral fat was noted to occur despite a normal body mass index and the absence of metabolic disease. Yamamoto et al 20 showed that there is increased secretion of adiponectin in the mesenteric adipose tissues of CD patients. Growth hormone levels have been shown to correlate negatively with intra-abdominal fat in male CD patients not on steroids and appear to have an important role in modulating visceral fat distribution in these patients. 21 It has been hypothesized that abnormal local concentrations of adiponectin could result in up-regulated production of TNF-, and this could promote damage to the mucosa, with an increased risk of developing complications like fistulas. Whether visceral fat accumulation is a consequence of CD or is involved in the pathogenesis of this disease is still unclear, but visceral fat accumulation is higher in CD patients with fistulas or strictures, and a higher visceral to subcutaneous fat ratio is a marker of complicated CD. Prospective multicenter studies will need to be done to confirm the findings of this study and assess the utility of the MFI to predict disease behavior and act as a prognostic tool for patients with CD. Limitations to our study include the small number of patients from a single center and the retrospective design. However, the visceral and subcutaneous fat areas were measured by a researcher blinded to the information on the patients, and the outcomes (complicated or inflammatory CD) were determined by another researcher blinded to the measurements. Because this was retrospective, we did not have reliably measured body mass index data or waist-hip ratio of many of these patients and therefore could not compare the value of these measurements with the MFI. Duration of disease is another potential confounder that could have influenced the results. However, simi- Figure 2. (A) Scatterplot of MFI by age (at time of CT scan) labeled according to disease behavior (complicated or inflammatory). (B) Scatterplot of MFI by duration of disease (at time of CT scan) labeled according to disease behavior (complicated or inflammatory).

4 August 2011 MESENTERIC FAT IN CROHN S DISEASE 687 lar to Desreumaux et al, 2 we did not find any association between intra-abdominal fat and duration of disease on a multivariate analysis. Steroid use by some patients could have influenced the results of this study. However, intra-abdominal fat accumulation in CD appears to be independent of steroid use. Katznelson et al 21 have previously shown that intra-abdominal to total body fat ratio in 20 male CD patients not on steroids was significantly higher than in matched healthy controls. Desreumaux et al also did not find any correlation between steroid therapy and importance and distribution of abdominal fat tissue. Finally, abdominal fat distribution varies by ethnicity, 22 and because a majority of patients in our study were white, these results might need to be verified in other ethnic populations as well. This study adds to the increasing evidence that visceral fat might have a more active role to play in CD. Serial measures of visceral fat area and the MFI might help elucidate whether this is a secondary phenomenon or is central to the development of complicated and more severe forms of CD. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: / j.cgh References 1. Crohn BB, Ginzburg L, Oppenheimer GD. Landmark article October 15, 1932: regional ileitis a pathological and clinical entity. JAMA 1984;251: Desreumaux P, Ernst O, Geboes K, et al. Inflammatory alterations in mesenteric adipose tissue in Crohn s disease. Gastroenterology 1999;117: Sheehan AL, Warren BF, Gear MW, et al. Fat-wrapping in Crohn s disease: pathological basis and relevance to surgical practice. Br J Surg 1992;79: Schaffler A, Herfarth H. Creeping fat in Crohn s disease: travelling in a creeper lane of research? Gut 2005;54: Borley NR, Mortensen NJ, Jewell DP, et al. The relationship between inflammatory and serosal connective tissue changes in ileal Crohn s disease: evidence for a possible causative link. J Pathol 2000;190: Breese EJ, Michie CA, Nicholls SW, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 1994;106: Karmiris K, Koutroubakis IE, Kouroumalis EA. The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel disease. Inflamm Bowel Dis 2005;11: Schaffler A, Furst A, Buchler C, et al. Secretion of RANTES (CCL5) and interleukin-10 from mesenteric adipose tissue and from creeping fat in Crohn s disease: regulation by steroid treatment. J Gastroenterol Hepatol 2006;21: Sjostrom L, Kvist H, Cederblad A, et al. Determination of total adipose tissue and body fat in women by computed tomography, 40K, and tritium. Am J Physiol 1986;250:E736 E Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999; 211: Dusserre E, Moulin P, Vidal H. Differences in mrna expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 2000;1500: Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007;116: Koda M, Senda M, Kamba M, et al. Sonographic subcutaneous and visceral fat indices represent the distribution of body fat volume. Abdom Imaging 2007;32: Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19(Suppl A): Blain A, Cattan S, Beaugerie L, et al. Crohn s disease clinical course and severity in obese patients. Clin Nutr 2002;21: Hass DJ, Brensinger CM, Lewis JD, et al. The impact of increased body mass index on the clinical course of Crohn s disease. Clin Gastroenterol Hepatol 2006;4: Moore LL, Bradlee ML, Singer MR, et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord 2004;28: Giovannucci E, Ascherio A, Rimm EB, et al. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995;122: Moon HG, Ju YT, Jeong CY, et al. Visceral obesity may affect oncologic outcome in patients with colorectal cancer. Ann Surg Oncol 2008;15: Yamamoto K, Kiyohara T, Murayama Y, et al. Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn s disease. Gut 2005;54: Katznelson L, Fairfield WP, Zeizafoun N, et al. Effects of growth hormone secretion on body composition in patients with Crohn s disease. J Clin Endocrinol Metab 2003;88: Katzmarzyk PT, Bray GA, Greenway FL, et al. Racial differences in abdominal depot-specific adiposity in white and African American adults. Am J Clin Nutr 2010;91:7 15. Reprint requests Address requests for reprints to: Venkataraman Subramanian, MD, DM, MRCP(UK), Nottingham Digestive Diseases Centre, E Floor, West Block, Nottingham University Hospital, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom. v.subramanian@ nottingham.ac.uk; fax: 44 (0) Conflicts of interest The authors disclose no conflicts.

5 August 2011 MESENTERIC FAT IN CROHN S DISEASE 687.e1 Supplementary Figure 1. Receiver operating characteristic (ROC) curve for MFI in identifying patients with complicated CD.

Visceral Fat as a Useful Parameter in the Differential Diagnosis of Crohn s Disease and Intestinal Tuberculosis

ORIGINAL ARTICLE ISSN 1598-9100(Print) ISSN 2288-1956(Online) http://dx.doi.org/10.5217/ir.2014.12.1.42 Intest Res 2014;12(1):42-47 Visceral Fat as a Useful Parameter in the Differential Diagnosis of Crohn