Diagnosis and management of inflammatory bowel diseases (IBD) is based on a combination of clinical symptoms, laboratory tests, endoscopic findings, and radiographic imaging. Although the gold standard of defining clinical remission in IBD is based on the clinical symptoms, recent interest focused on mucosal healing as a key endpoint in the management and long-term outcomes in IBD, including limiting hospitalizations and decreasing the risk of surgery.1 Repeated assessment by endoscopy is invasive, impractical, and limited in the extent of the gastrointestinal (GI) tract that can be evaluated, so this has led to increased interest in other noninvasive endpoints in treating IBD, including serologic markers (C-reactive protein),2 stool studies (fecal calprotectin),3 and diagnostic imaging. In addition, clinical trials have shown that clinical symptoms and endoscopic inflammation may show a lack of correlation during medical therapy,4 so the increased interest in diagnostic imaging as a noninvasive marker of disease activity in IBD is warranted.
Traditionally, diagnostic imaging in IBD included x-rays, ultrasound (US), and the use of barium-based fluoroscopic examinations (e.g., small bowel follow-through [SBFT]). These studies were limited in their sensitivity of disease assessment, operator dependent, and not as frequently used in medical practice. With the inception of the computed tomography (CT) in the 1970s and widespread availability of commercial scanners, the use of radiographic assessment has revolutionized the management of both Crohn's disease (CD) and ulcerative colitis (UC). The technological advantage of CT scanning led to the Nobel prize in 1979 and followed a remarkable rise in the number of CT scans performed nationwide. In the United States, it is estimated that 85 million CT scans were performed in 2011 compared with 3 million CT scans in 1980.5 This exponential rise in the use of CT scans has brought additional benefits but has also brought new concerns. Specifically, CT scans deliver much higher doses of diagnostic medical radiation (DMR), which is a form of ionizing radiation that may increase the risk of cancer development for both blood cancers (leukemia and lymphoma) and solid tumors.6–9
Patients with IBD are at increased risk of radiation exposure from repeat radiographic imaging, which will be the focus of this review. The overall risk of cancer development related to DMR exposure is currently very controversial, but the widespread and frequent use of CT scans in the management of IBD have made discussing the risks of radiation exposure for patients with IBD essential. Gastroenterologists need to be informed regarding the risks and benefits of radiographic imaging in IBD to help their patients make an informed decision regarding the risks and benefits of diagnostic radiographic imaging.
THE RISKS OF DMR
The risk of any one CT scan is not large, but the massive increase in use of CT scans has made the risk of DMR a public health concern. There are 2 significant controversies regarding DMR that could both greatly impact the risk of malignancy derived from radiation exposure: (1) the amount of radiation exposure from different radiographic studies varies widely in the literature and (2) the risk of increased malignancy at high cumulative radiation exposure differs greatly between studies. These 2 areas of debate have created a significant amount of confusion regarding the actual risk of malignancy for both patients and clinicians.
Amount of Diagnostic Radiation Exposure Per Study
DMR has various measurements to describe the radiation dose delivered, including the absorbed dose, effective does, and CT dose index. The absorbed dose, which is measured in grays equals 1 J of radiation energy absorbed per kilogram, is difficult to calculate as the radiation given by CT scan is not evenly distributed. The effective dose, measured in sieverts or millisieverts, is more accurate for DMR and is a generic estimate of radiation exposure to the patient. The amount of DMR for most common radiographic imaging studies in gastroenterology is controversial with a wide range in reported exposure from different studies.10,11 For example, a CT scan ranges from 2 to 20 mSV.12 The dose is in part difficult to calculate because the actual dose of radiation each organ receives is based largely on the models13 and will differ based on the patient-specific factors, such as size, weight, and fat distribution. In addition, CT protocols vary and use a variety of different techniques to attempt to reduce the radiation exposure following the principle as low as reasonably achievable.14,15
For the most commonly ordered studies in patients with IBD, a summary of the approximate radiation exposure is listed in Table 1. To further complicate the issue in IBD, is increasing use of a specialized CT scanning, CT enterography (CTE). CTE allows for much clearer imaging of mucosal disease activity, fistulas, or abscesses because it combines high-resolution CT scanning with multiplanar reconstructions after ingestion of a high-volume negative contrast agent. It is not surprising that CTE is highly correlated with mucosal disease activity and disease complications in prospective studies.17–19 However, CTE exposes patients with IBD to even higher dose of DMR than routine CT scan. Fortunately, several recent studies have shown that modified low-dose protocols reduced radiation exposure by 31% to 64% in Crohn's patients by either changing the noise reduction or automatic exposure control during the acquisition of images.20,21 These studies are encouraging as they show that the amount of radiation exposure can be significantly lowered during CTE, but they also point to the wide variance in radiation exposure and how some patients may be getting exposed to higher than normal doses of DMR for this specialized study.
Risk of Malignancy from DMR
The original studies that documented an increased risk of malignancy from ionizing radiation were done in Japan from survivors of the atomic bombs dropped in Hiroshima and Nagasaki in 1945.22,23 Large epidemiological studies have now followed these survivors for over 50 years after their exposure, and based on the distance from the blast center, an equivalent dose of ionizing radiation can be calculated. As DMR is also ionizing radiation, epidemiological data are often used as a comparison for DMR, but this comparison remains controversial.24,25 The model based on the atomic bomb survivors is the linear no-threshold risk model. A second model, the threshold response model, is based on an increased risk of cancer existing only above a certain threshold. The linear no-threshold model found an increased risk of cancer at doses as low as 35 mSV or 1 to 2 CT scans, which the threshold response model would not support. Between these 2 models, the linear no-threshold was supported by the National Academy of Science Biological Effects of Ionizing Radiation (BEIR) VII report and reported that there is likely some risk of increased malignancy even at low levels of radiation.26
The lifetime attributable risk of cancer from radiation exposure estimates the excess cancer risk above the baseline in the population. Based on the epidemiological data from survivors of the atomic bomb in Japan, a significant increase risk in cancer, particularly leukemia, lymphoma, and solid tumors, was seen with exposure to ionizing radiation.27 Most cancers derived from DMR are in those organs or tissues with rapid replicating cells like the bone marrow and intestinal tract. This is because ionizing radiation causes damage to double-stranded DNA during replication28 and will therefore affect faster replicating cells more frequently. For this reason, the age of exposure to radiation is a critical factor to determine cancer risk. Not only do most cancer derived from DMR exposure have a long latency period but also at a younger age our cells replicate more quickly. Therefore, at younger age of exposure, the risk of cancer may be 5-fold greater than exposure as an adult. A recent study by Pearce et al29 showed that CT scans in childhood that delivered a 50 mSv cumulative dose tripled the risk of leukemia and brain cancer. Based on these findings, the risk for a young child (<5 years) getting a brain cancer from a CT scan was 1 in 1000 and decreased to 1 in 2000 at age 15. The roughly 3-fold increase in the relative risk of cancer had an overall low absolute risk as these are rare cancers, but the risk of cancer from DMR was authenticated.
RISK OF DIAGNOSTIC RADIATION EXPOSURE IN IBD
Patients with IBD are at particular risk for high levels of exposure to DMR and from malignancy derived from DMR. This is because IBD is often diagnosed at a young age,30 is a lifelong disease with no known cure, and has a waxing and waning disease course with frequent episodes of disease flare31 necessitating repeated and frequent radiological examination. Repeated CT, x-ray, and fluoroscopic barium examinations are often required in patients with IBD and in particular in those with CD to assess for a disease flare, exclude abscess or bowel obstruction, determine extent of disease involvement, identify perioperative complications, or access response to therapy. Several studies have identified that patients with IBD are already at risk of specific cancers, such as colorectal and small intestinal cancers.6,7 Furthermore, immunosuppressive and biological agents used in management of IBD have been linked to other malignancies, such as GI cancers, skin cancer, and lymphoma, including fatal hepatosplenic lymphomas.32,33 Therefore, there is a specific concern for harmful effects of DMR in the IBD population, particularly when repeated exposures to DMR could increase the risk of cancers in a population already at risk.
Studies Evaluating the Cumulative Radiation Exposure in Patients with IBD
Studies evaluating DMR exposure in IBD are summarized Table 2. Similar to the general population, in patients with IBD, the diagnostic modality of choice to evaluate the abdomen has shifted in favor of CT scans. Data from the Mayo clinic for patients with IBD demonstrate a decrease in SBFT examinations (2800 studies in 2003–2004 to 975 studies in 2007) and an increase in CTE during the same period of time (375 studies in 2003 to 3166 studies in 2007).35 This increase use of CTE is primarily for patients with CD, and thus not surprisingly, patients with CD seem to be at increased risk of higher levels of ionizing radiation over patients with UC. Risk factors for high doses of DMR in patients with CD include gender, age of diagnosis, disease distribution, disease behavior, family history of IBD, history of previous surgery,36 and use of biologics or immunomodulators41,42 (Table 3). These factors are those associated with more severe disease course, which would necessitate more frequent and repeated emergency room (ER) visits, hospital admissions, and more frequent radiological examinations like CT.
Desmond et al34 evaluated radiation exposure in 409 patients with CD in Ireland, from 2002 to 2007, and found an increased use of CT scans of nearly 400% during their study period. In addition, the mean cumulative dose of diagnostic radiation received by patients was 36.1 mSv with 15.5% of patients exceeding 75 mSV. These dosages were comparable with other occupational studies in nuclear industry workers who were at risk of protracted low-dose radiation exposure (50–75 mSv) and demonstrated an increased cancer-related mortality.43 The study also demonstrated that patients were more likely to receive excessive radiation exposure when they required at least 1 course of oral steroids or intravenous steroids, infliximab, or >1 CD-related surgery.34 Another study by Palmer et al37 from an insurance claim database analyzed radiation exposure in children with IBD and found that 34% of patients with CD and 23% of patients with UC were exposed to moderate diagnostic radiation, >20 mSv. This study found an association of moderate radiation exposure with hospitalization, emergency department encounter, surgery, and use of steroids. A retrospective study performed by Kroeker et al38 assessed the total effective dose of ionizing radiation from imaging in patients with IBD over a 5-year period and found that patients with CD had more frequent exposure to CT scans in comparison with patients with UC (34% and 20%, respectively), with previous surgery as a notable predictor of excessive radiation exposure. A study by Levi et al36 evaluated patients in a tertiary center in Israel and found that surgery, prednisone use, and first year of diagnosis were all independent predictors of increased exposure to DMR in IBD. Most recently, an excellent meta-analysis of DMR exposure in patients with IBD demonstrated that 8.8% of patients with IBD from several studies received potentially harmful levels of radiation, defined as >50 mSv, which is equivalent to 3 to 5 CT scans of the abdomen.44
STRATEGIES TO LIMIT RADIATION EXPOSURE IN IBD
The 2 main ways to avoid radiation exposure in IBD are to (1) determine if a radiographic study is necessary and (2) choose an imaging study that limits radiation exposure when possible. The most obvious way to limit radiation exposure is to limit unnecessary CT scans. The most common location for patients, including those with IBD, to get a CT scan is in the ER.45,46 The number of CT scans performed in the ER has markedly increased in the last several decades. For example, a recent study in patients with IBD found a 165% increase in CT scans in the ER over a roughly 10-year period.47 Several studies have found that patients receive repeated CT scans during their repeated ER visits with no objective benefit from these repeated exposures to ionizing radiation. A recent study in 648 patients with CD assessed in the ER showed that despite an almost doubling of CT scan use from 47% in 2001 to 78% in 2009, the rate of management altering findings (perforation, obstruction, abscess) did not differ between the 2 time periods, at 29.0% and 34.9%, respectively, nor did the rate of hospital admission.48 Another study focusing on the outcome of CT scans for abdominal pain in the ER showed a very low yield of 8.4% and 4.9% for the second and the third repeat CT scans, respectively, in a non-IBD cohort49 compared with the first CT, which had a diagnostic yield of 22.5%. These studies point to the potential overuse of CT scans in the ER and low increase in yield of CT scan findings despite a rapid increase in the number of CT scan being preformed. Indeed, a recent interesting prospective study from the University of Pennsylvania showed that by creating a simple “reminder tool” in the electronic medical record that mentioned the adverse effects of cumulative radiation from CT scanning and the low yield from repeat CT scans for abdominal pain, investigators were able to decrease the number of CT scans in the ER by 10%.50 These studies also highlighted an urgent need to establish a validated pathway to narrow the use of CT scanning in IBD during ER visits and hospital admissions.
The second way to limit DMR exposure in IBD is to choose a different radiographic examination than CT scans—magnetic resonance imaging (MRI) of abdomen, magnetic resonance enterography (MRE), or abdominal US; all of which do not expose patients with IBD to ionizing radiation. The pros and cons of these alternative radiographic imaging modalities to CT are listed in Table 3 and discussed below.
ALTERNATIVES TO CT SCANNING
CTE has become the test of choice for accurate assessment of the small bowel in patients with CD because it not only can detect severe complications like an abscess or a fistula but it can also detect subtle mucosal lesions or a mild intestinal stricture. However, CTE exposes patients to considerable ionizing radiation. To avoid radiation exposure, similar protocols using magnetic resonance technology have been developed. MRE like CTE allows for a combination of high-resolution imaging with high-volume oral contrast agent. Cross-sectional imaging modalities available in CT and MRI have become increasingly important in diagnosing complications of IBD that often require acute intervention, such as abscesses, fistulas, or bowel perforation.51 The most significant advantage in MRI over CT is the lack of radiation exposure in MRI. Historically, MRI of the abdomen was limited by extensive motion artifact from respiration and long acquisition times.52 Consequently, the role of MRI in IBD was limited mainly to the evaluation of perianal disease in Crohn’s with a pelvic MRI as the pelvis is not subject to breathing aperistaltic motion. However, over the past decade, MRI sequencing has been dramatically improved, providing high-resolution motion-free images to better evaluate the entire bowel.53
Indeed, recent advances in magnetic resonance technology have increased its image resolution that is now comparable with CT imaging. Multiple prospective studies have demonstrated MRE to be better or at least comparable with other imaging modalities in evaluation of small bowel disease in patients with CD. Berstein et al54 compared MRE with fluoroscopic barium small bowel series in 30 subjects and found that 10 studies were normal by both modalities and 8 studies showed similar extent of CD by both tests. SBFT revealed additional information in 4, whereas MRI provided clinically relevant added information in 8, including identifying active inflammation in structured areas based on the wall enhancement patterns, lymphadenopathy, and vasa recta changes. MRE also allows dynamic evaluations of small bowel peristalsis and dispensability of areas of luminal narrowing and intraluminal masses to better assess the severity and characteristics of intestinal strictures.55 Comparison of MRI and single-phase helical CT scanning demonstrated MRI to be superior for detection of subtle bowel inflammatory changes.56 In another study, a prospective comparison of MRE and CTE showed MRE to be equally as sensitive as CTE in detecting mucosal abnormalities in CD, but MRE was even more sensitive than CTE in detecting strictures or ileal inflammation (mucosal enhancement).57 Therefore, GI imaging with MRE in IBD has significant advantage not only for assessing treatment response by the presence and severity of mucosal inflammation through abnormal enhancement patterns but also for assessing the ileum and cecum in patients difficult to reach by colonoscopy.58 Unfortunately, limitations of MRE in comparison with CT include higher cost, potentially less radiologist experience with the MRE protocols, and less geographic availability of high resolution required to do these procedures. Furthermore, long examination times and residual intraluminal air may limit the use of MRI in patients who are critically ill or those with acute and severe exacerbations of their disease.59 However, the use of MRE when it is feasible would significantly decrease the number of CT examinations and thus decrease radiation exposure in patients with IBD.
US provides another alternative modality to CT to evaluate the GI tract in IBD. Dedicated US examination of GI tract in patients with IBD is capable of identifying extraintestinal complications of IBD and assessing the extent and severity of mucosal abnormalities including the depth of mucosal involvement that could be highly useful to differentiate Crohn's colitis with transmural involvement from UC with superficial mucosal involvement.60 One study conducted by highly experience GI ultrasonographers reported that US can detect small or large bowel inflammation in patients with suspected or proven IBD in the range of 78% to 96% and 89% to 100%, respectively.61 Unfortunately, abdominal US may also provide false-negative results when the mucosal lesions are superficial or in obese patients, even in the hands of an experienced radiologist.62 The use of oral contrast agents such as iso-osmolar polyethylene glycol solution may increase sensitivity in defining disease extent, lesion site, and bowel complications of CD,63 but concerns over false negatives, operator expertise, lack of protocols in most medical centers has limited its widespread use.
Traditional SBFT with oral barium contrast historically has been the modality of choice to assess inflammatory or structural lesions in patients with suspected or documented CD. Evaluation of small bowel by barium follow-through in conjunction with fluoroscopy and manual palpation to compress the individual loops properly has been clinically accepted for patients with suspected or proven diagnosis of IBD.59 SBFT also has the benefit of being associated with small effective radiation exposure of 3 mSv.64 In Europe, small bowel enteroclysis (SBE), rather than SBFT, has been the preferred mode of evaluation of the small bowel in IBD since 1980s. SBE relies primarily on abnormalities in bowel mucosal pattern and intestinal caliber.65 It poses an advantage of detecting early mucosal pathologies of CD including aphthous ulcerations or mucosal granularity and short strictures in small bowel. However, these techniques are insensitive for detecting transmural inflammation or extraluminal complications in IBD.66 In addition, SBE in particular requires placement of a nasogastric tube, which is invasive and uncomfortable and thus highly unpopular with patients. Also, because it requires extensive fluoroscopic time, radiation exposure can be significantly higher than SBFT, and the utility of SBE is limited in centers where MRE is easily available.
Finally, capsule endoscopy (CE) has also emerged as an adjunctive tool in evaluating the small bowel and may aid in providing useful knowledge in patients with suspected CD or for assessing the extent and severity of disease.67 Evidence has suggested that findings of CE may impact the management of patients with CD. For example, normal small bowel in CE in symptomatic patients with documented CD would spare these patients from unnecessary change in their anti-inflammatory medication. Indeed, 48% of 134 symptomatic patients previously diagnosed with CD by SBFT or ileocolonoscopy had normal small bowel in CE.68 In contrast, 52% of the patients with CD were found to have significant small bowel ulcerations in their CE that led to a change in treatment. Furthermore, a meta-analysis found that CE had higher sensitivity for detecting small bowel lesions than small bowel radiography, CTE, or colonoscopy with ileoscopy when it was used in the evaluation of suspected or established patients with CD.69 A recent study found that CE detected small bowel lesions in 24% of the patients with CD with perianal disease (e.g., abscesses, fistulas, recurrent fissures) who had normal SBFT on ileoscopy, SBFT, or CTE/MRE.70 There are several important limitations for the use of CE. These include a lack of accessibility and the risk of capsule retention in a stricture, a risk that is increased in patients with IBD.71
The risk of DMR brings several challenging ethical issues regarding informed consent. Patients should be informed of risks and benefits of all the tests they receive including a CT scan. First, the risks of DMR should be discussed with the patient. Second, clinicians should include the patient in the decision making regarding the choice of radiological imaging when appropriate. Although this is a controversial issue due to a concern that patients will misinterpret the actual risk and refuse needed imaging, a recent editorial in JAMA has highlighted several key points in regards to this issue.72 The intent of informed consent is clear that adequate information about any test that a reasonable person would want to know should be provided to the patient before it being performed. This requires that all risks and benefits of diagnostic medical imaging are outlined and alternatives are discussed. The lack of informed consent in diagnostic imaging is highlighted by the findings of a recent cross-sectional study in patients in the ER for abdominal pain that found that 70% of patients underestimated the radiation exposure delivered by one CT scan, and 39% of the patients who reported having no previous CT imaging had had a CT examination in the past when their medical records were reviewed.73 Currently, informed consent is not necessary to obtain a CT scan, but informing patients about the risks of DMR is important for clinicians to consider in the future.
Patients with IBD, particularly CD, are at increased risk of high cumulative doses of DMR. Young age is the greatest risk factor for the development of a malignancy from ionizing radiation; therefore, patients diagnosed at a young age with IBD, who often have a more aggressive disease course, are at the greatest risk of a future malignancy from radiation exposure. Other identifiable risk factors for high radiation exposure in IBD include the use of immunomodulators, use of biologics, or a history of multiple surgeries. The exact risk of malignancy from high exposure to DMR remains controversial, based on the available data ranges from very high to very low. However, some increased risk of malignancy is present, and given this risk, alternative forms of imaging such as MRE, US, or CE should be considered in patients with IBD. Establishing a validated pathway to narrow the use of CT scanning during hospitalization or visits to the ER is needed in patients with IBD. In the meantime, physicians need to carefully consider the risks and benefits of a CT scan, particularly when evaluating a young patient with CD who has identifiable risk factors for an aggressive disease course.
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