The failure of gastroenterologists to apply intestinal ultrasound in inflammatory bowel disease in the Asia-Pacific: A need for action

Transcription

1 bs_bs_banner doi: /jgh SOLICITED REVIEW The failure of gastroenterologists to apply intestinal ultrasound in inflammatory bowel disease in the Asia-Pacific: A need for action Anil Kumar Asthana,*, Antony B Friedman,*, Giovanni Maconi, Christian Maaser, Torsten Kucharzik, Mamoru Watanabe and Peter R Gibson*, *Department of Gastroenterology, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia; Gastroenterology Unit, Department of Biomedical and Clinical Sciences, Luigi Sacco University Hospital, Milan, Italy; Department of General Internal Medicine and Gastroenterology, University Teaching Hospital Lueneburg, Lueneburg, Germany; and Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan Key words abdominal abscess, computerized tomography, Crohn s disease, disease assessment, fistula, imaging modalities, intestinal ultrasound, magnetic resonance imaging, stricture, ulcerative colitis. Accepted for publication 16 December Correspondence Dr Anil Kumar Asthana, Department of Gastroenterology, Alfred Hospital, 55 Commercial Road, Melbourne, Vic. 3004, Australia. dranilasthana@gmail.com Abstract Intestinal ultrasound (IUS) is a cheap, noninvasive, risk-free procedure that is significantly underutilized in the diagnosis and management of patients with inflammatory bowel disease (IBD) in the Asia-Pacific region. More cost-effective methods of monitoring disease activity are required in light of the increasing global burden of IBD (especially in Asia), the advent of personalized medicine, and the rising cost of healthcare. IUS is a prime example of a technique that meets these needs. Its common clinical applications include assessing the activity and complications of IBD. In continental Europe, countries such as Germany and Italy use this imaging tool as the standard of care and have integrated it into management protocols. There are formal training programs in these countries to train gastroenterologists in IUS, and it is used in an outpatient setting during patient consultations. Barriers to its use in the Asia-Pacific region include lack of experience and research data, and there are few established centers with active training programs. These concerns can be addressed by investing more in IUS service provision and by increasing allocation of resources toward local research and training. Increased uptake of IUS will ultimately benefit patients with IBD. Introduction Intestinal ultrasound (IUS) is a cheap, noninvasive, and radiationfree imaging modality that is commonly used in continental Europe for the investigation and management of inflammatory bowel disease (IBD). It plays an important role in countries like Italy and Germany for the diagnosis, monitoring, and determination of response to treatment of IBD. 1 Due to lack of awareness, its use and acceptability remain limited in the rest of the world, including the United States, Canada, United Kingdom, Australasia, and Asia. This is despite the high level of evidence supporting its use in clinical practice: the European Crohn s and Colitis Organisation has endorsed its use in IBD and holds IUS workshops at its annual conferences. 2 At present, the prevalence and incidence of IBD is lower in Asia than in the West. 3 However, rates are rising faster in Asia than anywhere else in the world. 4 Combined with the fact that 60% of the world s population lives in Asia, the global burden of IBD is likely to significantly increase in the future. Australia has an IBD incidence rate of 29.6/ , which is one of the highest in the world. 5 Over the last 10 years, Australian health-care costs have risen by an extraordinary 70%. 6,7 Ballooning health-care costs are also seen in other countries in Asia. 6,8 Thus, in the Asia-Pacific region, there is an increasing demand for an accurate and relatively inexpensive imaging modality for diagnosis, monitoring, and management of IBD. The main barrier to the use of IUS in the Asia-Pacific region is the extreme lack of local expertise. There are few training centers and limited resources for clinicians and sonographers. As such, IUS and its applications are not well understood by many clinicians. This position paper aims to provide a brief overview of current evidence of the use IUS in IBD, training requirements and clinical applications in continental Europe, followed by suggestions for future directions for Asia-Pacific. Equipment, process, and skills for IUS The machines and probes required for an IUS examination are no different to the ones used in standard radiology departments and are available in most centers in the Asia-Pacific region. The examination technique involves use of both low-frequency curved probes (1 6 MHz) and high-frequency linear probes (5 13 MHz). 446 Journal of Gastroenterology and Hepatology 30 (2015)

2 The abdomen is first scanned using the low-frequency probe in order to detect any deep or grossly abnormal pathology such as significant bowel wall thickening, intra-abdominal fistulae, abscesses, or bowel dilatation. This is followed by detailed interrogation of the intestinal wall using a high-frequency probe and noting features such as specific bowel wall thickness measurements, fistulae, and prominent lymph nodes. 9 Although different systematic approaches are used, areas that are interrogated include the colon (left and right sides), terminal ileum, small bowel, mesentery, and mesenteric lymph nodes. Although prior sonographic experience is useful, ultrasound (US)-naïve clinicians can be trained to perform IUS competently after performing approximately 200 examinations under supervision. 10 Clinical utility of IUS IUS has many advantages over other imaging modalities, such as computerized tomography (CT) and magnetic resonance imaging (MRI). IUS is cheap and noninvasive, and, unlike any other modality, provides real-time motility imaging. IUS does not expose patients to radiation, and there are no risks involved, allowing it to be repeated whenever necessary. It also allows clinicians to obtain instant data (disease activity and extent), complimentary to known clinical information, in order to make further management decisions. To qualify as an attractive technology, IUS must be able to assess parts of the intestinal tract affected by IBD and it should be as accurate as other imaging modalities. It could even offer unique information. The capabilities of IUS in patients with IBD are summarized in Table 1. Limitations of IUS. Operator dependability is a significant limitation to performing IUS, as is the case with other sonographic examinations. The level of operator experience during training may be an important factor, and performing a minimum of 150 IUS scans during training can help achieve basic competence in IUS. 11 However, a follow-up study has not been performed to examine whether achieving this volume of IUS during training translates to improved reproducibility with IUS findings. Patient factors, such as obesity, have an adverse effect on the technical aspects of the procedure and hence its utility. The rectum may often be difficult to accurately assess with IUS because of its deep pelvic location and thus a particular limitation for ulcerative colitis patients. The transverse colonic segment may often be a challenging area to examine clearly. IUS has also been shown to be inferior to other cross-sectional imaging modalities for examination of the small bowel, 12 but small intestinal contrast ultrasound (SICUS) is an alternative that improves its accuracy. 13 Furthermore, CT has a higher sensitivity than IUS in diagnosing intestinal obstruction, 14 diverticulitis, and appendicitis, 15 whereas a good level of agreement has been demonstrated between transperineal ultrasound (TPUS) and MRI for assessment of perianal disease. 16 Defining activity of disease. Prospective studies have demonstrated that Crohn s disease may be diagnosed using IUS with a sensitivity of 67 96% and a specificity of % Figures 1 5 illustrate the imaging capabilities of IUS. No significant differences in diagnostic accuracy among IUS, CT, and MRI have been reported (Table 2). 23 The sensitivity and specificity of Table 1 Capabilities of intestinal ultrasound in patients with inflammatory bowel disease Assessment of disease activity Assessment of complications Unique information Advantages over other imaging modalities Disadvantages over other imaging modalities Good level evidence for assessment for all degrees of inflammation in small bowel and colon in Crohn s disease Increasing evidence base for assessment of colonic disease in ulcerative colitis Abscesses and differentiation from an inflammatory phlegmon using contrast Strictures with proximal bowel dilatation Enteric and perineal fistulae Perianal abscesses and inflammatory phlegmon (see above) Toxic megacolon Real-time data, such as motility Wall layer stratification Mesenteric hyperechogenicity Reactive lymphadenopathy Hyperemia on color Doppler Differentiation between abscesses and inflammatory phlegmon Inflammatory component of fistulae and strictures on color Doppler Fibrosis element of intestinal wall Cheap No radiation Completely risk-free No need for fasting or bowel preparation for most scans Operator dependent CT for the assessment of disease activity is 81 and 88%, and similarly, MRI is 80 and 82%, respectively. 24 IUS is increasingly becoming the first-line investigation in suspected Crohn s disease for early diagnosis. 25 The salient features of active disease include the presence of a thickened bowel wall and increased vascularization. 26 The degree of thickness correlates well with endoscopic findings 24 and has a weak correlation with the Crohn s disease activity index Despite interobserver variability between various IUS indices, measurements of bowel wall thickness using IUS have good reproducibility. 29 A wall thickness of less than 3 mm is deemed normal. Using this as a cut-off value, IUS has a sensitivity of 88% and specificity of 93% with regard to diagnostic accuracy. 23,29 Using a bowel wall thickness of 4 mm as the diagnostic criterion for active disease gives a sensitivity of 75% and specificity of 97% 23,29 (Fig. 2). Assessment of the vascularity of thickened bowel wall segments with color Doppler is also useful in determining disease activity It can help differentiate between active and quiescent Crohn s disease; this has been accurately correlated with clinical and endoscopic scores in adults. 32 Assessment of the blood flow in the superior mesenteric artery using color Doppler US has been used to assess Crohn s disease activity with conflicting results SICUS, where the bowel is distended by prior ingestion of polyethylene glycol solution, is a means of improving the sensitivity of disease detection, particularly for Journal of Gastroenterology and Hepatology 30 (2015)

3 a Figure 1 Illustration of the individual intestinal wall layers; mucosa (hypoechoic), submucosa (hyperechoic), muscularis propria (hypoechoic), and serosa (hyperechoic). b Figure 2a&b Features of active inflammation in and around the descending colon. Crohn s disease in jejunum and proximal small bowel, and for accurate assessment of strictures. 22 Although SICUS increases diagnostic accuracy, 37 its clinical value in IBD has not yet been established. 38 IUS in ulcerative colitis has shown promising results, although it is less validated than in Crohn s disease The colonic segments proximal to the rectosigmoid junction can be easily visualized with IUS to assess disease activity. The rectum can often be challenging to view because of its deep pelvic location, and the low-frequency probe is used in these instances. Due to the superficial nature of inflammation, wall stratification is more preserved in contrast to that in Crohn s disease; 38 however, active disease is associated with increased bowel wall thickness. 42 Improved accuracy rates have been demonstrated for assessment of disease activity and extension in ulcerative colitis compared with Crohn s disease patients, using both MRI and IUS. 41 A prospective trial in patients with moderate to severe ulcerative colitis illustrated that the IUS score at 3 months predicted both disease outcome and endoscopic activity at 15 months. 39,40 This raises the possibility of IUS becoming a noninvasive marker for mucosal healing in ulcerative colitis. TPUS is a modality that can be used for assessment of perianal Crohn s disease (PACD). A high-frequency probe is placed at the anal verge (in both transverse and longitudinal views), and the perineum is assessed for the presence of fistulae or abscesses. Anatomical structures that are routinely examined include the anal canal, the internal and external anal sphincters, anorectal junction, the distal rectum, and the ischiorectal fossae (Fig. 5). Good correlation of perianal fistulae detection compared with surgical findings has been demonstrated with diagnostic accuracy ranging from approximately 85% to 94%. 16,43,44 TPUS has also demonstrated good agreement with MRI in the assessment of PACD. 16 In particular, TPUS has a unique advantage in the detection of superficial perirectal sepsis 45 but can overdiagnose trans-sphincteric fistulae, whereas MRI may overdiagnose extrasphincteric fistulae. 45 TPUS thus offers a cheap, noninvasive, and safe alternate imaging modality, which may be used in the diagnosis and monitoring of PACD. Assessing complications of disease. IUS is a useful tool to detect IBD-related intra-abdominal complications including strictures, fistulae, abscesses, mesenteric hyperechogenicity, and reactive lymphadenopathy. It is particularly good at detecting both severe strictures (with associated prestenotic bowel dilatation) with an accuracy of greater than 90% 25,46 48 and enteric fis- 448 Journal of Gastroenterology and Hepatology 30 (2015)

4 Figure 5 A normal transperineal ultrasound. Figure 3 Terminal ileal stricture with proximal intestinal dilatation. Table 2 Comparison of the accuracies of intestinal ultrasound (IUS), computerized tomography (CT), and magnetic resonance imaging (MRI) for the diagnosis of inflammatory bowel disease (IBD) IUS (%) CT MRI P value Mean sensitivity for diagnosis NS Mean per patient specificity NS estimates 23 Mean per-bowel segment sensitivity NS estimates 23 Mean per-bowel segment specificity estimates NS NS, not significant. Figure 4 Fistulizing Crohn s disease. tulae, particularly enteromesenteric fistulae, 49 with a sensitivity of 87% and specificity of 90% 46 (Fig. 3). SICUS further improves the accuracy of detecting fistulae and strictures, 50 whereas intravenous contrast-enhanced ultrasound has the ability to differentiate abscesses from inflammatory phlegmons. 51 Compared with colonoscopy, postoperative disease recurrence can be reliably detected using SICUS with a sensitivity of 92.5% and positive predictive value of 94%. 26 Doppler sonography has been used for assessment of hypervascularization and inflammation in diseased bowel wall segments; in particular, features such as the flow volume, velocity or resistance, and pulsatility index on spectral analysis in both small and large vessels have helped diagnose IBD. 52 Figures 3 and 4 show examples of the assessment of complications of Crohn s disease. Current use and training in Europe Two countries where the application of IUS is widespread and an integral part of IBD management are Germany and Italy. In Germany, all gastroenterologists and internal medical trainees are trained in US. In order to become a qualified specialist in internal medicine, one is required to perform 500 supervised abdominal US (this includes IUS) and 150 supervised thyroid US. 53 To become a qualified gastroenterologist, one must perform 200 supervised abdominal US in addition to 50 supervised US-guided abdominal punctures, including liver biopsies. The Landesärztekammer (State Chamber of Physicians) sets the qualification standards, whereas the German Society for Ultrasonography in Medicine offers further subspecialized training in ultrasonography as well as a platform for collaborative US research between centers. This infrastructure fosters training, education, and research in IUS. In Italy, IUS is used in the management of IBD in two settings the outpatient clinic itself and in elective outpatient lists. During an IBD consultation in clinic, the patient will have a US performed by the physician. Combined with a history, physical examination, and biochemical tests, the addition of IUS allows the clinician to visualize the intestinal tract in real-time and manage the disease accordingly. Patients and clinicians in Italy prefer the use of IUS as a first-line investigation, and subsequent imaging (CT or MRI) is requested in the event of obscurity or complexity in IUS findings. 54 Thus, costs are minimized and patient convenience is optimized by not having to visit the radiology department on another day. IUS is used for primary diagnosis, monitoring of disease, detection of Journal of Gastroenterology and Hepatology 30 (2015)

5 extraintestinal complications (such as abscesses and fistulae), assessment of the small bowel proximal to the terminal ileum, perianal disease diagnosis and monitoring using TPUS, preoperative work-up using TPUS, and assessment of disease response. The need for IUS Standard of care in IBD today consists of a treat-to-target strategy. 55 The primary target is mucosal healing as assessed by endoscopy, which reveals both the level and location of activity. There are, however, risks involved with this procedure, 56 and it cannot reach beyond the distal ileum. Furthermore, it only addresses the mucosa, which may be inadequate for a transmural disease such as Crohn s disease. Fecal calprotectin is increasingly utilized for the assessment of IBD activity, but its performance as a surrogate for endoscopy is yet to be validated and it provides no information regarding location of disease. 57 On the other hand, IUS when compared with endoscopic remission has an overall accuracy of 86.4% with an AUROC of 0.87 for Crohn s disease. A bowel wall thickness of less than 3 mm predicts mucosal healing with 95.5% accuracy. 58 Thus, IUS may potentially act as a risk-free proxy for endoscopy in determining both the level of activity (including the deeper layers of the intestinal wall) and location of disease. Increasing complexity and personalization of care based on the treat-to-target principle in IBD has led to greater utilization and frequency of monitoring at the intestinal level. Imaging modalities such as colonoscopy, CT, and MRI are used for this purpose. 2,59,60 Colonoscopy is expensive, time consuming for the patient, and can have major complications (e.g., perforation, bleeding, and anesthetic complications) leading to significant morbidity and even mortality. MRI is time consuming, noisy, and claustrophobic. Contrast-induced nephrotoxicity is a risk of both MRI and CT. 61,62 The level of ionizing radiation exposure with CT is significant, and at least 10% of IBD patients are exposed to potentially harmful levels of diagnostic medical radiation. 63 This is even more concerning for pediatric patients, where a single CT scan has been shown to increase a child s overall risk of cancer by 24% in the first 10 years after the CT. 64 Based on the above risks in combination with increasing health-care costs, an alternative imaging modality is needed. IUS is non-invasive, radiation-free, and inexpensive and is therefore an ideal imaging modality, especially in pregnancy and pediatric cohorts. Images are real-time and extraintestinal features such as abscesses, mesenteric hyperechogenicity, and reactive lymphadenopathy can be seen. IUS can also be used to assess the bowel proximal to strictures, which is often impossible at endoscopy. Importantly, endoscopy can only provide information regarding the mucosa and may miss significant transmural Crohn s disease, which is easily visualized with IUS. Although IUS can theoretically examine the entire gastrointestinal tract, some segments, such as the rectum and proximal ileum, are more difficult to visualize. A limitation of IUS is that accuracy is compromised in patients with a high body mass index, which is not experienced with CT and MRI. For all three modalities, there is the concern of interoperator variability, which can be overcome by rigorous training and internal auditing. Compared to endoscopy in IBD, there is a dearth of standardized scoring systems for abnormal findings on IUS. Current situation and future directions in Asia-Pacific Australia is an example of a country in the Asia-Pacific region where IUS is underutilized. The Alfred Hospital, Melbourne, is the only Australian hospital to offer a regular IUS service to IBD patients. This service is driven by gastroenterologists (AKA and ABF) who, between them, sought their major training in Italy and Germany. Australian gastroenterologists have a limited awareness and trust in IUS because of the dearth of local data and experience. The published data on IUS training has derived from a highly experienced European group, which is of relevance because there is a considerable learning curve for IUS. 10 Hence, resources need to be directed to specific centers to develop IUS services. Established centers require infrastructure funding and formalized training programs to be able to offer, for example, dedicated fellowship positions and educational activities for other clinicians to promote IUS. To fully acknowledge its true potential, a regular service for IBD patients is required, as well as local studies with documentation of accuracy compared with gold standards such as colonoscopy. With multiple accredited centers, concepts such as total bowel wall healing, rather than just mucosal healing as documented at colonoscopy can be explored. As IUS is cheap, noninvasive, and easily reproducible, IUS-based prognostic and treatment algorithms could be developed to further individualize care for IBD patients. In Asia, IUS is currently well established for the assessment of conditions such as parasitic infections. When compared with CT or MRI, the accuracy of IUS is considered to be more dependent on the patients body mass index in diagnosing conditions such as appendicitis. Because the Asian population has a lower BMI than the European population, especially in the southeastern region, IUS accuracy for evaluation of IBD in such areas should be investigated; this would be best done via multinational and multicenter trials. IUS is considered to be a valuable modality in evaluating suspected and established IBD patients in rural Asia, where costly modalities such as CT and MRI are not available. IUS is also very useful in evaluating pregnant IBD patients who may present with flares of disease. In Asia, the combination of limited resources, large populations, and a rising incidence and prevalence of IBD necessitates the need for uptake of IUS. This would occur with the establishment of centers for formal training and service provision. Undertaking collaborative research with centers from other non- Asian countries would also assist in increasing the uptake of IUS and awareness in Asia. Conclusion IUS is an imaging modality that has been successfully used for many years in continental Europe in the management of IBD. However, it is significantly underutilized in the rest of the world. Factors that make IUS potentially the optimal imaging modality for IBD patients are that it is cost-effective, noninvasive, and easily reproducible. IUS allows for frequent monitoring to optimize care based on objective markers of disease activity and treating to therapeutic targets. It is safer for patients than other imaging modalities, which pose the hazards of ionizing radiation (CT), contrast-induced nephrotoxicity (CT and MRI) as well as the 450 Journal of Gastroenterology and Hepatology 30 (2015)

6 multiple risks of colonoscopy and associated anesthesia. However, its limitations, particularly with regard to operator dependability and examination of some areas of the bowel, such as the rectum and proximal small bowel, must be factored into its application. Local data are required to confirm its accuracy and illustrate its utility in IBD as well as formulating its integration into treatment protocols. This will enable increased awareness and uptake of IUS by clinicians across the Asia-Pacific region, providing a considerable benefit to patients with IBD. References 1 Maconi G, Terracciano F, de Sio I et al. Referrals for bowel ultrasound in clinical practice: a survey in 12 nationwide centres in Italy. Dig. Liver Dis. 2011; 43: Panes J, Bouhnik Y, Reinisch W et al. Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence-based consensus guidelines. J. Crohns. Colitis. 2013; 7: Prideaux L, Kamm MA, De Cruz PP et al. Inflammatory bowel disease in Asia: a systematic review. J. Gastroenterol. Hepatol. 2012; 27: SC N. Epidemiology of inflammatory bowel disease: focus on Asia. Best Pract. Res. Clin. Gastroenterol. 2014; 28: Wilson J, Hair C, Knight R et al. High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study. Inflamm. Bowel Dis. 2010; 16: Moreno N, Ripolles T, Paredes JM et al. Usefulness of abdominal ultrasonography in the analysis of endoscopic activity in patients with Crohn s disease: changes following treatment with immunomodulators and/or anti-tnf antibodies. J. Crohns. Colitis. 2014; 8: Welfare AIoHa. Health Expenditure Australia : Analysis by Sector. Health and welfare expenditure series no. 51. Cat. no. HWE 60. In: Welfare AIoHa, ed. Canberra: AIHW, Han K, Cho M, Chun K. Determinants of health care expenditures and the contribution of associated factors: 16 cities and provinces in Korea, J. Prev. Med. Public Health 2013; 46: Maconi G, Greco S, Duca P et al. Prevalence and clinical significance of sonographic evidence of mesenteric fat alterations in Crohn s disease. Inflamm. Bowel Dis. 2008; 14: Monteleone M, Friedman AB, Furfaro F et al. The learning curve of intestinal ultrasonography in assessing inflammatory bowel disease preliminary results. J. Crohns. Colitis. 2013; 7: S Monteleone MFA, Furfaro F, Dell Era A, Bezzio C, Maconi G. The learning curve of intestinal ultrasonography in assessing inflammatory bowel disease preliminary results. ECCO Abstract, Allen PB, De Cruz P, Lee WK et al. Noninvasive imaging of the small bowel in Crohn s disease: the final frontier. Inflamm. Bowel Dis. 2011; 17: Calabrese E, Zorzi F, Pallone F. Ultrasound of the small bowel in Crohn s disease. Int. J. Inflam. 2012; 2012: Suri S, Gupta S, Sudhakar PJ et al. Comparative evaluation of plain films, ultrasound and CT in the diagnosis of intestinal obstruction. Acta Radiol. 1999; 40: van Randen A, Lameris W, van Es HW et al. A comparison of the accuracy of ultrasound and computed tomography in common diagnoses causing acute abdominal pain. Eur. Radiol. 2011; 21: Maconi G, Tonolini M, Monteleone M et al. Transperineal perineal ultrasound versus magnetic resonance imaging in the assessment of perianal Crohn s disease. Inflamm. Bowel Dis. 2013; 19: Bozkurt T, Richter F, Lux G. Ultrasonography as a primary diagnostic tool in patients with inflammatory disease and tumors of the small intestine and large bowel. J. Clin. Ultrasound 1994; 22: Hata J, Haruma K, Suenaga K et al. Ultrasonographic assessment of inflammatory bowel disease. Am. J. Gastroenterol. 1992; 87: Pera A, Cammarota T, Comino E et al. Ultrasonography in the detection of Crohn s disease and in the differential diagnosis of inflammatory bowel disease. Digestion 1988; 41: Sheridan MB, Nicholson DA, Martin DF. Transabdominal ultrasonography as the primary investigation in patients with suspected Crohn s disease or recurrence: a prospective study. Clin. Radiol. 1993; 48: Solvig J, Ekberg O, Lindgren S et al. Ultrasound examination of the small bowel: comparison with enteroclysis in patients with Crohn disease. Abdom. Imaging 1995; 20: Sonnenberg A, Erckenbrecht J, Peter P et al. Detection of Crohn s disease by ultrasound. Gastroenterology 1982; 83: Horsthuis K, Bipat S, Bennink RJ et al. Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology 2008; 247: Panes J, Bouzas R, Chaparro M et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn s disease. Aliment. Pharmacol. Ther. 2011; 34: Parente F, Greco S, Molteni M et al. Oral contrast enhanced bowel ultrasonography in the assessment of small intestine Crohn s disease. A prospective comparison with conventional ultrasound, x ray studies, and ileocolonoscopy. Gut 2004; 53: Calabrese E, Petruzziello C, Onali S et al. Severity of postoperative recurrence in Crohn s disease: correlation between endoscopic and sonographic findings. Inflamm. Bowel Dis. 2009; 15: Drews BH, Barth TF, Hanle MM et al. Comparison of sonographically measured bowel wall vascularity, histology, and disease activity in Crohn s disease. Eur. Radiol. 2009; 19: Rigazio C, Ercole E, Laudi C et al. Abdominal bowel ultrasound can predict the risk of surgery in Crohn s disease: proposal of an ultrasonographic score. Scand. J. Gastroenterol. 2009; 44: Fraquelli M, Sarno A, Girelli C et al. Reproducibility of bowel ultrasonography in the evaluation of Crohn s disease. Dig. Liver Dis. 2008; 40: Martinez MJ, Ripolles T, Paredes JM et al. Assessment of the extension and the inflammatory activity in Crohn s disease: comparison of ultrasound and MRI. Abdom. Imaging 2009; 34: Migaleddu V, Scanu AM, Quaia E et al. Contrast-enhanced ultrasonographic evaluation of inflammatory activity in Crohn s disease. Gastroenterology 2009; 137: Neye H, Voderholzer W, Rickes S et al. Evaluation of criteria for the activity of Crohn s disease by power Doppler sonography. Dig. Dis. 2004; 22: Byrne MF, Farrell MA, Abass S et al. Assessment of Crohn s disease activity by Doppler sonography of the superior mesenteric artery, clinical evaluation and the Crohn s disease activity index: a prospective study. Clin. Radiol. 2001; 56: Karoui S, Nouira K, Serghini M et al. Assessment of activity of Crohn s disease by Doppler sonography of superior mesenteric artery flow. J. Crohns. Colitis. 2010; 4: Maconi G, Parente F, Bollani S et al. Factors affecting splanchnic haemodynamics in Crohn s disease: a prospective controlled study using Doppler ultrasound. Gut 1998; 43: Journal of Gastroenterology and Hepatology 30 (2015)

7 36 van Oostayen JA, Wasser MN, van Hogezand RA et al. Activity of Crohn disease assessed by measurement of superior mesenteric artery flow with Doppler US. Radiology 1994; 193: Maconi G, Radice E, Bareggi E et al. Hydrosonography of the gastrointestinal tract. AJR Am. J. Roentgenol. 2009; 193: Strobel D, Goertz RS, Bernatik T. Diagnostics in inflammatory bowel disease: ultrasound. World J. Gastroenterol. 2011; 17: Parente F, Molteni M, Marino B et al. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-to-severe forms of ulcerative colitis?: a prospective study. Am. J. Gastroenterol. 2010; 105: Parente F, Molteni M, Marino B et al. Bowel ultrasound and mucosal healing in ulcerative colitis. Dig. Dis. 2009; 27: Pascu M, Roznowski AB, Muller HP et al. Clinical relevance of transabdominal ultrasonography and magnetic resonance imaging in patients with inflammatory bowel disease of the terminal ileum and large bowel. Inflamm. Bowel Dis. 2004; 10: Andreoli A, Cerro P, Falasco G et al. Role of ultrasonography in the diagnosis of postsurgical recurrence of Crohn s disease. Am. J. Gastroenterol. 1998; 93: Nevler A, Beer-Gabel M, Lebedyev A et al. Transperineal ultrasonography in perianal Crohn s disease and recurrent cryptogenic fistula-in-ano. Colorectal Dis. 2013; 15: Stewart LK, McGee J, Wilson SR. Transperineal and transvaginal sonography of perianal inflammatory disease. AJR Am. J. Roentgenol. 2001; 177: Plaikner M, Loizides A, Peer S et al. Transperineal ultrasonography as a complementary diagnostic tool in identifying acute perianal sepsis. Tech. Coloproctol. 2014; 18: Gasche C, Moser G, Turetschek K et al. Transabdominal bowel sonography for the detection of intestinal complications in Crohn s disease. Gut 1999; 44: Kohn A, Cerro P, Milite G et al. Prospective evaluation of transabdominal bowel sonography in the diagnosis of intestinal obstruction in Crohn s disease: comparison with plain abdominal film and small bowel enteroclysis. Inflamm. Bowel Dis. 1999; 5: Maconi G, Bollani S, Bianchi Porro G. Ultrasonographic detection of intestinal complications in Crohn s disease. Dig. Dis. Sci. 1996; 41: Maconi G, Greco S, Parente F et al. [Bowel ultrasound in Crohn s disease. Surgical importance]. Ann. Ital. Chir. 2003; 74: Pallotta N, Vincoli G, Montesani C et al. Small intestine contrast ultrasonography (SICUS) for the detection of small bowel complications in Crohn s disease: a prospective comparative study versus intraoperative findings. Inflamm. Bowel Dis. 2012; 18: Piscaglia F, Nolsoe C, Dietrich CF et al. The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall. Med. 2012; 33: Di Sabatino A, Armellini E, Corazza GR. Doppler sonography in the diagnosis of inflammatory bowel disease. Dig. Dis. 2004; 22: Landesarztekammer tscop. 54 Maconi G, Bolzoni E, Giussani A et al. Accuracy and cost of diagnostic strategies for patients with suspected Crohn s disease. J. Crohns. Colitis. 2014; 8: Mosli MH, Sandborn WJ, Kim RB et al. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am. J. Gastroenterol. 2014; 109: Arora G, Mannalithara A, Singh G et al. Risk of perforation from a colonoscopy in adults: a large population-based study. Gastrointest. Endosc. 2009; 69: Smith LA, Gaya DR. Utility of faecal calprotectin analysis in adult inflammatory bowel disease. World J. Gastroenterol. 2012; 18: Moreno N, Ripolles T, Paredes JM et al. Usefulness of abdominal ultrasonography in the analysis of endoscopic activity in patients with Crohn s disease: changes following treatment with immunomodulators and/or anti-tnf antibodies. J. Crohns. Colitis. 2014; 8: Butcher RO, Nixon E, Sapundzieski M et al. Radiation exposure in patients with inflammatory bowel disease primum non nocere? Scand. J. Gastroenterol. 2012; 47: Bouguen G, Levesque BG, Feagan BG et al. Treat to target: a proposed new paradigm for the management of Crohn s disease. Clin. Gastroenterol. Hepatol. 2013; doi: /j.cgh Shabana WM, Cohan RH, Ellis JH et al. Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am. J. Roentgenol. 2008; 190: Parfrey PS, Griffiths SM, Barrett BJ et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N. Engl. J. Med. 1989; 320: Chatu S, Subramanian V, Pollok RC. Meta-analysis: diagnostic medical radiation exposure in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2012; 35: Mathews JD, Forsythe AV, Brady Z et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 346: f Journal of Gastroenterology and Hepatology 30 (2015)