Applied Radiology

The last decade has seen many advances in the pathophysiology, treatment, and imaging of Crohn's disease. This article will review these recent advances and suggest imaging strategies and findings that will help radiologists assist internists, surgeons, and gastroenterologists caring for patients with Crohn's disease.

Pathophysiology of Crohn's disease

Crohn's disease is thought to result from genetic susceptibility as well as a complex interaction between enteric flora and the gut. These factors lead to an altered immune response that causes mucosal and transmural inflammation of the bowel.

Genetic susceptibility

In the late 1990s, several groups from the United States and abroad discovered nucleotide polymorphisms within a gene on chromosome 16, conferring Crohn's disease susceptibility in affected sibling pairs. ¹ This gene, called Nod-2 (or CARD-15), is an intracellular protein in lymphocytes. Homozygosity for mutation in the Nod-2 gene leads to susceptibility for Crohn's disease that is 20 to 40 times normal. The Nod-2 gene plays a role in binding bacterial endotoxins, and potentially in apoptosis (programmed cell death). ² The Nod-2 gene also initiates a cascade that produces tumor necrosis factor-alpha (TNF-*), the potent inflammatory cytokine that is markedly elevated in Crohn's disease. Mutations in the Nod-2 gene result in decreased binding of bacterial antitoxins. Other foci of genetic susceptibility for Crohn's disease exist, but their role is unclear. ³

Gut­flora interaction

Enteric flora also play an important role in the development of Crohn's disease. ⁴ Clinical response to antibiotics, and diminished bowel inflammation subsequent to fecal diversion, demonstrate the pro-inflammatory role enteric flora can play. Patients with Crohn's disease have increased mucosal permeability to bacteria, resulting in increased interaction between bacteria and the mucosa. Some investigational therapies entering human clinical trials are aimed at changing the composition of enteric flora, employing probiotics (including Lactobacillus ) to decrease inflammation. ^5-7

New therapies for Crohn's disease

There is a panoply of new therapies for Crohn's disease. Their targets range from the gut lumen and the modulation of enteric flora (eg, probiotics and antibiotics), to global downregulation of inflammatory response (eg, purine synthesis inhibitors such as azathioprine, 6-mercaptopurine) to a full range of targeted antibodies. ^8,9

Infliximab is a chimeric antibody composed of a human constant portion and a murine variable portion, which binds to human TNF-*. Clinical trials have shown infliximab to be effective in treating moderate, severe, fistulizing, and refractory Crohn's disease. One early study found that 81% of patients with moderate or severe Crohn's disease responded to therapy, with nearly half of the patients entering remission 4 weeks after a single infusion of the drug. ¹⁰ Multiple doses of infliximab are usually necessary for treatment of fistulizing disease, with more than half of fistulas demonstrating closure. ¹¹ Multiple dosing is sometimes required to maintain remission. ¹²

The alpha-4 integrins are a class of leukocyte adhesion molecules that are thought to help mediate the migration of inflammatory cells from the capillaries of the gut into the lamina propria. ⁹ In early clinical trials, natalizumab, an anti-alpha-4 integrin antibody, has shown promise as a treatment for Crohn's disease. ¹³

Challenges for the gastroenterologist

The principle challenge for the gastroenterologist in patients with Crohn's disease is to determine if symptoms are due to active disease that is medically or surgically treatable. There has consequently arisen a large array of activity indices for Crohn's disease that seek to correlate biological inflammation with symptoms, fistulous disease, and endoscopic severity. ¹⁴ Histologic assessments of Crohn's disease do not correlate well with other estimates of disease activity, and clinical activity indices rely upon subjectivity of both the patient and the physician.

Challenges for the radiologist

Identifying only the presence or absence of Crohn's disease is no longer adequate. Given the major advances in pathophysiologic understanding of Crohn's and the development of targeted biologic therapeutic agents, it is incumbent upon radiologists to identify active inflammation, as well as disease complications that alter the selection of medical and/or surgical therapies. Accurately characterizing the cause of bowel stenosis and the nature of any extraenteric complications will help clinicians make appropriate therapeutic choices as they treat patients with Crohn's disease.

Cross-sectional imaging

The improved spatial and temporal resolution of computed tomography (CT) and magnetic resonance (MR) scanners now allow the detection of some mucosal disease. Mucosal disease is identified by mucosal hyperenhancement and thickening, while transmural disease is characterized by bowel-wall thickening, mural stratification, transmural ulcers, and hyperemic vasa recta (the "comb sign"). As radiologists, we need to translate our visual paradigm of active disease at fluoroscopy to the cross-sectional modalities (Figure 2).

Mucosal hyperenhancement is best identified when using a negative contrast agent in the bowel lumen and intravenous (IV) contrast. Mucosal enhancement can be confidently identified when the bowel lumen is distended and the mucosa is hyperenhancing compared with adjacent normal-appearing small bowel. With transmural inflammation, mural stratification will often accompany mucosal
hyperenhancement (Figure 3). Mural stratification, also called the target sign, refers to hyperenhancement of the mucosa and muscularis propria with decreased attenuation of the submucosa, representing either submucosal edema or fat (Figure 4). Mural stratification indicates that transmural fibrosis has not yet occurred. ¹⁶ When the low attenuation of the mucosa resembles edema and is accompanied by hyperemia in the vasa recta and mucosal hyperenhancement, one can be confident active inflammation is present.

We have found the hyperemic vasa recta, or "comb sign," to be a helpful finding in patients with active disease (Figure 5). ¹⁷ Lee et al ¹⁸ recently found that hyperemic vasa recta correlated positively with the symptom severity, aggressive treatment, and length of hospital stay. Barium findings correlating with the hyperemic vasa recta included mesenteric border linear ulcers, perpendicular ulcerations, and long segments of Crohn's disease.

Bowel-wall thickening is the least specific sign of Crohn's disease. When we encounter sporadic bowel-wall thickening, we exclude vascular compromise before considering Crohn's disease. When accompanied by other signs more specific for Crohn's disease, inflammatory bowel disease can be suggested.

Paraenteric findings of Crohn's disease included fibrofatty proliferation, mild adenopathy, fistula, phlegmon, and abscess. In a large surgical series, fibrofatty proliferation was highly specific for Crohn's disease of the small bowel. ¹⁹ Fibrofatty proliferation, like linear ulcers, occurs along the mesenteric border (Figure 6). Fibrofatty proliferation may not simply represent a benign reaction to adjacent inflammation, but may promote intestinal inflammation, as TNF-* is also produced in the perienteric fat. ²⁰ Fibrofatty proliferation associated with the rectum and sigmoid, unlike the mesenteric border distribution of fatty proliferation in the small bowel, may appear circumferential.

Cross-sectional imaging has long been used to identify phlegmon and abscess as complications of Crohn's disease. We find that with the speed and smaller slice thicknesses available with multidetector CT, we see more interloop abscesses as well as their connection with the bowel lumen. Small abscesses will likely respond to antibiotics and anti-inflammatory therapy.

Fistulizing disease

While radiologists are comfortable with identifying fistulas as tracts containing barium and positive enteric contrast, we need to be more comfortable identifying fistulas using negative oral contrast agents and IV contrast. In this setting, fistulas appear as linear, hyperenhancing extraenteric tracts connecting bowel to bowel, or bowel to other structures. When performing CT of the abdomen and pelvis in Crohn's patients, it is imperative to scan through the perineum to identify fistulous perianal disease (Figure 7).

Perianal anatomy is best demonstrated on MR imaging. The internal anal sphincter is contiguous with the inner circular muscle of the rectum and demonstrates slightly hyperintense T2 signal compared with the external sphincter. It also demonstrates intense enhancement after gadolinium (Figure 8). The external sphincter, puborectalis, and levator ani muscles demonstrate uniformly low signal and enhance minimally with gadolinium. Fistulas are described by their Parks classification ²¹ (which describes the relationship of a fistula to the sphincters and puborectalis), external openings on the skin, and internal openings in the anorectum (Figure 9). Small, simple fistulas below the level of the puborectalis (ie, superficial, intersphincteric, and transsphincteric fistulas) can often be treated successfully with antibiotics, 6-mercaptopurine (or azathioprine) and infliximab, without surgical treatment. ²² They may also be treated with a fistulotomy if the sphincters are not involved. When patients have proctocolitis, or fistulas extend more superiorly (posing a greater risk to sphincter integrity), a noncutting seton is typically employed, in addition to medical therapy. A noncutting seton is a suture that passes through the fistula and the anal canal, allowing the fistula to drain, preventing premature fistula closure and abscess formation. Abscesses are usually treated with incision and drainage when they are superficial, or a catheter drainage when deeper. Proctocolectomy is usually reserved for severe recurrent disease. Many fistulas cause horseshoe tracts or abscesses about the anal rectum (Figure 10).

We typically image perianal fistulas with a noninvasive protocol employing a phased-array torso coil, fast spin-echo imaging with fat saturation in three planes, with a slice thickness of 5 mm and a skip of 0 mm. ²³ These images are used for fistula detection. A corresponding set of axial fast spin-echo images without fat saturation is used to classify the fistula according to its relationship to the puborectalis and anal sphincters. Finally, we obtain two-dimensional (2D) spoiled gradient-recalled (SPGR) images after gadolinium in axial and coronal planes. When employing this noninvasive protocol, the performance of MR is similar to endoscopic ultrasound (EUS) or examination under anesthesia. ²³ One advantage of MR over EUS is that it often demonstrates systemic complications (Figure 11).

Many complications of Crohn's disease are unsuspected at the time of imaging. Crohn's patients are at increased risk for colon and small-bowel cancers as well as lymphoma. ²⁴ They are also prone to the development of several hepatobiliary complications including cholelithiasis, hepatic abscess, and primary sclerosing cholangitis (PSC). Approximately 1% of Crohn's patients will develop PSC, and approximately 10% of the patients with PSC have Crohn's. ²⁵ Crohn's patients are also prone to pancreatitis and nephrolithiasis. Toxic megacolon is one complication that can be difficult to diagnose at cross-sectional imaging. Findings include colonic dilation, loss of the normal haustral markings, and pericolonic inflammatory stranding. These findings should prompt plain-film correlation, if necessary. Sacroiliitis is another important complication to recognize, as it can predate the development of enteric disease.

CT and MR enterography

MR and CT enterography are high-resolution, cross-sectional studies of the small bowel performed after small-bowel enema. Small-bowel enema can be achieved either through the placement of a nasojejunal tube and the infusion of methylcellulose, or by having the patient ingest a large volume of oral contrast over a specified period of time. ^26-31 A negative oral contrast agent should be employed, in conjunction with IV contrast material, so that mucosal hyperenhancement and mural stratification can be easily recognized.

We recently performed a feasibility study of CT enterography, with some of the patients receiving a 1800 mL methylcellulose infusion via nasojejunal tube and the remainder receiving four 450 mL aliquots of water at 75, 50, 25, and 10 minutes prior to CT scanning. ²⁸ Both groups of patients received IV glucagon immediately prior to a contrast-enhanced CT scan. Luminal distention was similar between the two groups of patients. ²⁸ Additionally, the accuracy of both techniques was between 80% and 90% for detecting active Crohn's disease in the neoterminal ileum, compared with ileoscopy, which served as the gold standard. Small-bowel follow-through in these patients had an accuracy of 74%. CT enterography identified more fistulas and more abscesses than small-bowel follow-through, and was equally sensitive in identifying partial small-bowel obstruction. The volume challenge of enterography improves the sensitivity of MR or CT for partial obstruction as well as active inflammation. In addition, cross-sectional imaging provides direct visualization of loops deep in the pelvis, which are often difficult to evaluate fluoroscopically.

Findings at CT and MR enterography are as previously described with MR and CT, except they are more conspicuous. Additionally, the jejunal and ileal fold patterns are demonstrated in the distended small bowel (Figure 12). Jejunal loops can sometimes falsely appear thickened due to a combination of prominent valvulae conniventes and peristalsis. When a question arises, a delayed scan through the region of interest usually resolves any concerns.

We now offer CT enterography as a routine clinical test. Scanner room time is the same as a standard CT of the abdomen and pelvis, but patients arrive 90 minutes early to begin oral hydration. We believe that CT enterography works well in Crohn's patients because there is a degree of intrinsic obstruction due to bowel inflammation, and we observe, anecdotally, that the small bowel is not as well distended in some normal patients without any underlying bowel obstruction or inflammation. Multiple investigators are examining the use of additives, osmotic agents, and/or nonabsorbable fluids as oral agents for MR and CT enterography. ^26,30,32 We believe these new oral agents will greatly aid the assessment of Crohn's disease and other small-bowel pathologies in the future (Figure 13).

Conclusion

Crohn's disease develops as a result of genetic susceptibility and gut-flora interactions. These factors lead to an exaggerated inflammatory response by the host immune system. Targeted biological therapies, such as infliximab, are now used to treat many patients who would previously have gone to surgery. The role of the radiologist is to identify medically treatable disease, as well as complications that will require surgical intervention. The optimization of radiologic studies tailored to the clinical question (eg, cross-sectional enterography for imaging of the small bowel, and MR with phased-array coil for the imaging of perianal disease), allows radiologists to detect active disease and its complications with a high degree of accuracy. Understanding the pathophysiology of Crohn's and modern treatments will help radiologists assist clinicians in treating these patients, who often present with protean and nonspecific symptoms.